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Dopamine as a Prolactin (PRL) Inhibitor

Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati Medical Center, Cincinnati, Ohio 45267

Correspondence: Address all correspondence and requests for reprints to: Dr. Nira Ben-Jonathan, Department of Cell Biology, 3125 Eden Avenue, University of Cincinnati, Cincinnati, Ohio 45267-0521. E-mail: Nira.Ben-Jonathan{at}uc.edu

	Abstract

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
Dopamine is a small and relatively simple molecule that fulfills diverse functions. Within the brain, it acts as a classical neurotransmitter whose attenuation or overactivity can result in disorders such as Parkinson’s disease and schizophrenia. Major advances in the cloning and characterization of biosynthetic enzymes, transporters, and receptors have increased our knowledge regarding the metabolism, release, reuptake, and mechanism of action of dopamine. Dopamine reaches the pituitary via hypophysial portal blood from several hypothalamic nerve tracts that are regulated by PRL itself, estrogens, and several neuropeptides and neurotransmitters. Dopamine binds to type-2 dopamine receptors that are functionally linked to membrane channels and G proteins and suppresses the high intrinsic secretory activity of the pituitary lactotrophs. In addition to inhibiting PRL release by controlling calcium fluxes, dopamine activates several interacting intracellular signaling pathways and suppresses PRL gene expression and lactotroph proliferation. Thus, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators, none of which has yet emerged as a primary PRL releasing factor. The generation of transgenic animals with overexpressed or mutated genes expanded our understanding of dopamine-PRL interactions and the physiological consequences of their perturbations. PRL release in humans, which differs in many respects from that in laboratory animals, is affected by several drugs used in clinical practice. Hyperprolactinemia is a major neuroendocrine-related cause of reproductive disturbances in both men and women. The treatment of hyperprolactinemia has greatly benefited from the generation of progressively more effective and selective dopaminergic drugs.

I. Introduction

II. Characteristics of Dopaminergic Neurons

A. Synthesis and metabolism

B. Storage and exocytosis

C. Transporters

D. Receptors

III. The Hypothalamo-Pituitary Dopaminergic Systems

A. Anatomy and ontogeny

B. Physiology and pharmacology

C. Regulation by PRL

D. Effects of ovarian steroids

E. Interactions with neuropeptides and neurotransmitters

IV. Dopamine and the Pituitary Lactotrophs

A. Dopamine and its receptor

B. Actions and signal transduction

C. Antiproliferative activity

V. Lessons Learned from Transgenic Mice

A. Dopamine D₂ receptor (D₂R) and transporter

B. PRL and PRL receptor (PRL-R)

C. ERs, galanin, and nerve growth factor (NGF)

VI. Clinical Aspects

A. PRL physiology in humans

B. Drug-induced PRL release

C. Hyperprolactinemia and pituitary prolactinomas

D. Treatment of hyperprolactinemia

VII. Summary and Perspectives

	I. Introduction

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
DOPAMINE, NOREPINEPHRINE, AND epinephrine belong to a class of neurotransmitters known as catecholamines, which are structurally defined by a catechol ring and an amine side chain. Catecholamines and indolamines (i.e., serotonin) are referred to as monoamines. Monoamines are small, water-soluble molecules that are the decarboxylated derivatives of amino acids. Production from their respective amino acids is catalyzed by several enzymes that act in sequence, the first of which serves as the rate-limiting step. Monoamines are stored at high concentrations in secretory granules. These granules provide protection against degradation by metabolic enzymes and enable a regulated release via exocytosis. Like other neurotransmitters, monoamines act very rapidly and their action can be terminated by both metabolic conversion to inactive compounds as well as by reuptake into the producing cell.

Dopamine is synthesized primarily in the central nervous system (CNS), but limited production also occurs in the adrenal medulla. Dopamine is also detectable in a few non-neuronal tissues, e.g., the pancreas and the anterior pituitary. Dysfunction of dopaminergic systems is associated with a number of diseases. For example, deficiency of dopamine in midbrain nigrostriatal neurons has long been recognized in the pathogenesis of Parkinson’s disease, while overactivity of the limbic and cortical dopaminergic neurons has been implicated in schizophrenia and psychoses. These dopaminergic neurons are also affected by neurotoxins, psychostimulants, and drugs of abuse. In the neuroendocrine axis, dysfunction of hypothalamic dopamine or its pituitary receptors leads to hyperprolactinemia and reproductive disturbances. It is not surprising, therefore, that this relatively simple molecule has been at the center of interest of basic scientists and clinicians alike for many years.

Within the brain, catecholamines function as classical neurotransmitters, i.e., they communicate between neurons and act within the anatomically confined space of the synapse. However, by virtue of their presence in the circulation and action on distant target organs, catecholamines from the adrenal medulla were among the first compounds classified as hormones in the early 1900s. Not until the 1970s, however, did the role of dopamine as an inhibitor of the pituitary lactotrophs become recognized. Since then, dopamine has been clearly established as the primary regulator of PRL gene expression and release. On the other hand, among the many factors capable of stimulating PRL, none has emerged as a leading candidate for a PRL releasing factor (PRF). Therefore, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators.

In 1985, we published a review in this journal entitled "Dopamine: A Prolactin Inhibiting Hormone" (1). The present update covers pertinent information that has been gathered since the publication of this report. During the last 15 yr, this field has witnessed unparalleled progress, including the cloning of dopamine and PRL receptors (PRL-Rs), the characterization of the dopamine transporter, the recognition of the role that estrogen and its receptors play in PRL homeostasis, and the generation of transgenic animals deficient in all these genes. In terms of therapeutic applications, dopaminergic agonists have become the mainstay treatment for suppressing PRL in hyperprolactinemic patients and for shrinking prolactinomas.

The review is organized in five chapters. The first chapter covers advances in the understanding of dopamine synthesis, storage, release, reuptake, and receptor binding. The second and third chapters focus on the hypothalamo-pituitary dopaminergic systems, their regulation by various factors, and the mechanisms by which dopamine affects the lactotrophs. Lessons learned from transgenic animals with altered genes that are relevant to PRL regulation constitute the fourth chapter. Finally, the profile of PRL release in humans, clinical aspects of dopaminergic drugs, and the pathophysiology of hyperprolactinemia are presented in the fifth chapter. Since 1985, over 4000 articles have been published on various aspects of dopamine-PRL interactions. By necessity, this review is selective rather than inclusive. Consequently, the reader is referred whenever possible to other reviews for more in-depth coverage of the different topics.

	II. Characteristics of Dopaminergic Neurons

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
A. Synthesis and metabolism
Dopamine biosynthesis begins with the amino acid tyrosine (see Fig. 1). The majority of circulating tyrosine originates from dietary sources, but small amounts are derived from hydroxylation of phenylalanine by the liver enzyme phenylalanine hydroxylase (for review, see Ref. 2). Tyrosine enters neurons by an energy-dependent uptake process and is converted to dopamine by two enzymes that act in sequence, tyrosine hydroxylase (TH) and L-aromatic amino acid decarboxylase, also called dihydroxyphenylalanine (DOPA) decarboxylase (DDC). Neurons that contain active dopamine ß-hydroxylase (DBH) convert dopamine to norepinephrine, and those that also contain phenylethanolamine N-methyl transferase convert norepinephrine to epinephrine. The latter are classified as noradrenergic and adrenergic neurons, respectively, and their distribution in the brain differs considerably from that of the dopaminergic neurons. Regardless of the catecholamine being produced, TH is the rate-limiting step in their biosynthetic pathway.

View larger version (22K): [in this window] [in a new window]   Figure 1. Diagram of dopamine biosynthesis, release, and metabolism. 1) Tyrosine is taken into the neuron by a sodium-dependent mechanism; 2) conversion of tyrosine to L-DOPA by TH is the rate-limiting step in the biosynthetic pathway; 3) L-DOPA is converted to dopamine by DDC; 4) dopamine is translocated into secretory vesicles for storage, protection, and secretion; 5) fusion of secretory vesicles with the plasma membrane results in dopamine release into the synaptic cleft or the extracellular space ((s is the case with the TIDA neurons); 6) dopamine binds to its membrane receptors and initiates multiple effects in target cells; 7) unbound dopamine is taken up by the DAT, located in the plasma membrane of the presynaptic neuron; 8) both newly synthesized dopamine and that taken up into the cell are translocated into secretory vesicles by the VMAT; 9) MAO, located in the outer mitochondrial membrane, converts dopamine to a deaminated metabolite; 10) COMT converts dopamine or its deaminated metabolite to biologically inactive products.

The TH gene is localized to chromosome 11p in humans and encodes a single form of TH that can be alternatively spliced (5). Targeted disruption of the TH gene results in perinatal lethality, which can be rescued by L-DOPA administration (6). The mature enzyme is a soluble cytosolic protein composed of four subunits of approximately 60 kDa each (reviewed in Ref. 7). Each monomer is comprised of an inhibitory regulatory domain at the N terminus and a catalytic domain at the C terminus. The regulatory domain contains four phosphorylation sites located within the first 40 amino acids: Ser⁸, Ser¹⁹, Ser³¹, and Ser⁴⁰. The catalytic domain contains the pterin binding region and a putative leucine zipper at the C terminus that participates in intersubunit binding.

TH activity is the most critical factor that controls dopamine synthesis, and considerable efforts have been devoted to understanding activation/inactivation of this enzyme. TH activity is regulated by two mechanisms: short-term activation and long-term induction (for review, see Ref. 8). Activation (seconds to minutes) occurs in response to increased nerve impulses or pharmacological agents and involves removal of feedback inhibition by dopamine, allosteric regulation by polyanions, and phosphorylation. All phosphorylation sites, but especially Ser⁴⁰, are important for TH activation (9). Phosphorylation at specific sites is accomplished by several Ser/Thr kinases, e.g., PKA, PKC, ERK1/2, and calcium calmodulin-dependent protein kinase II, and results in conformational changes that alter enzyme affinity either to the pterin cofactor or to dopamine acting as an inhibitor (4). Because TH phosphorylation can be reversed by phosphatases, the activated state of TH at any given time reflects a dynamic balance between these antagonizing forces. As discussed in Section II.B, TH appears to be constitutively activated within the hypothalamo-pituitary unit, in sharp contrast with its normally quiescent state in both the striatum and adrenal medulla.

Long-term induction of TH involves transcriptional regulation, alternative RNA splicing, RNA stabilization, and translational regulation (for review, see Ref. 8). Nucleotide sequences up to 9 kb upstream from the transcriptional start site are necessary for developmental and tissue-specific control of TH expression. The promoter region contains several positive and negative transcriptional elements that are not conserved across species and differ among tissues (10). Changes in TH mRNA levels occur in response to alterations in physiological conditions, e.g., cold exposure and chronic stress, and are often mediated by glucocorticoids (11). Three major second messenger systems, cAMP, diacylglycerol, and calcium, which use a variety of effector molecules, have been implicated in this response. A combination of enzyme activation and long-term induction maintains dopamine synthesis by diverse and seemingly redundant tissue-specific mechanisms. These overlapping actions guarantee uninterrupted supply of the neurotransmitter and permit rapid neuronal responsiveness to many physiological stimuli.

As shown schematically in Fig. 1, DDC is the second and terminal enzyme in dopamine biosynthesis (reviewed in Ref. 12). The enzyme uses pyridoxal phosphate as a cofactor and can convert both DOPA to dopamine and 5-hydroxytryptophan to serotonin [5-hydroxytryptamine (5-HT)]. Although a single gene codes for the enzyme, there are several isoforms that may be responsible for preferred decarboxylation of either dopamine or serotonin. The mature enzyme is a dimer made of 50-kDa subunits and is regulated by de novo synthesis rather than by changes in its activity. Under basal conditions, enzyme activity is so high that L-DOPA is virtually undetectable.

Unlike dopamine, DOPA can cross the blood brain barrier, and this property has been exploited in the treatment of Parkinson’s disease, especially during the early stages when a sufficient number of midbrain dopaminergic neurons are still functional. To prevent rapid decarboxylation, DOPA has to be administered together with peripheral DDC inhibitors such as carbidopa or benserazide (13). Other DDC inhibitors, e.g., NSD 1015, have been widely used in laboratory animals for measuring DOPA accumulation as an index of dopamine biosynthesis (14). This approach is based on the findings that DOPA levels without drug application are virtually undetectable. Measurement of DOPA accumulation is well suited for evaluating dopaminergic neuronal activity in the median eminence and posterior pituitary, which contain only minimal levels of norepinephrine.

Catabolism is one of the effective mechanisms for dopamine inactivation (reviewed in Ref. 15). This involves multiple pathways that include oxidative deamination by monoamine oxidase (MAO), O-methylation by catechol-O-methyl transferase (COMT), and conjugation by sulfotransferases or glucoronidases. The preferred metabolic pathway at a given site depends on the compartmentalization of the metabolic enzymes. For example, MAO is located in the external membrane of the mitochondria and acts intracellularly, whereas COMT is associated with the external cell membrane and acts only extracellularly.

MAO exists as two isoenzymes, A and B, with an apparent molecular mass of 60–63 kDa each. The two MAO genes, each comprised of 15 exons, are located on the X-chromosome and appear to have been derived from the same ancestral gene (reviewed in Ref. 16). They differ in substrate specificity as well as selectivity for inhibitors. MAO-A is more highly expressed in catecholaminergic neurons, whereas MAO-B is more abundant in serotonergic and histaminergic neurons and in glial cells (17). Enzyme inactivation in humans or its deletion in transgenic mice are compatible with life but result in neurochemical and behavioral abnormalities (16). Deamination of dopamine by MAO produces dihydroxyphenylacetic acid (DOPAC). Determination of the ratio of DOPAC/dopamine concentrations serves as a good method for estimating rapid changes in neuronal activity, with a major advantage being that it does not require drug pretreatment. O-Methylation by COMT is primarily responsible for inactivation of circulating catecholamines. Consecutive conversion of dopamine by MAO and COMT yields homovanillic acid.

B. Storage and exocytosis
Because most endocrinologists are more familiar with peptide/protein hormones than with neurotransmitters, it is appropriate to compare the different characteristics of storage and exocytosis of these two classes of compounds. Dopamine is stored in secretory vesicles at a 100- to 1000-fold higher concentration than neuropeptides. This is attributed to several distinct features of monoaminergic neurons. First, unlike neuropeptides whose synthesis occurs within the endoplasmic reticulum and Golgi apparatus, dopamine biosynthesis can take place within the terminals themselves. Second, synthesis that occurs in a close proximity to the site of release permits a much faster turnover rate than the slow axoplasmic transport that brings proteins from cell bodies to the nerve terminals. Third, a unique reuptake process replenishes most of the released dopamine back into the secretory vesicles and maintains high intragranular concentration, whereas a released neuropeptide cannot be restocked.

After synthesis, dopamine is stored in synaptic vesicles at extremely high concentrations, 0.5–0.6 M, which is near its limit of solubility. Dopamine is translocated from the cytoplasm into the vesicles by the vesicular monoamine transporter (VMAT), shown schematically in Fig. 1 and discussed in detail in Section III.C. The function of the vesicles is 4-fold: 1) to protect dopamine from enzymatic degradation by MAO, 2) to minimize constitutive secretion by diffusion from the cells, 3) to facilitate regulated release, and 4) to enable rapid replenishment of depleted stores. The life cycle of the vesicles includes: 1) targeting to the active zone of the presynaptic membrane, 2) docking, 3) fusion, 4) release of the vesicular content, 5) retrieval by endocytosis, and 6) refilling with the neurotransmitter. Selected aspects of these events are discussed below. For a comprehensive coverage, please refer to several outstanding reviews (18, 19, 20, 21).

Monoamines are stored primarily in small translucent ("clear") vesicles (50–100 nm in diameter) but are also present in large dense core vesicles (up to 500 nm in diameter), often cosequestered with neuropeptides (22). The relationship between large and small vesicles, their predominance in catecholaminergic vs. neuroendocrine cells, their membrane composition, and their precise role in quantal neurotransmitter release are not clear. Also, most information on synaptic vesicles has been obtained from chromaffin cells, which contain primarily norepinephrine and epinephrine and differ from dopaminergic neurons by the presence of intravesicular DBH, chromogranins, and other constituents (23). It remains to be determined whether the content of the vesicles and the process of exocytosis are identical in dopaminergic and noradrenergic neurons.

Storage vesicles are formed in the neuronal perikarya and are transported to the terminals by slow axoplasmic flow. Although early studies suggested formation of vesicles from the outer membrane of the terminals by pinocytosis, it was later realized that this represented retrieval by endocytosis of previously fused vesicles. In fact, to maintain adequate transmitter storage and permit a sustained response to stimuli, endocytosis must occur at a rate that parallels exocytosis. The synaptic vesicle is a highly specialized structure whose membrane is composed of a lipid bilayer with embedded integral proteins that participate in vesicular trafficking, docking, and fusion. The vesicle membrane also contains an H⁺- ATPase, which maintains the proton gradient that energizes VMAT and preserves an acidic intravesicular environment. Each vesicle is filled with several thousand molecules of dopamine as well as other soluble constituents (24).

Much information has been gathered in recent years on the docking mechanism (reviewed in Refs. 18 and 25, 26, 27). It involves a family of proteins termed soluble N-ethylmaleimide-sensitive factor (NSF) attachment proteins (SNAP) receptors (SNARE) complexes: v-SNAREs, designating vesicular-associated proteins, and t-SNAREs, designating target (plasma membrane) cognate complexes. At least seven to eight proteins are essential for docking: vesicular synaptobrevin and synaptotagmin; SNAP-25 and syntaxin, which are located in both the vesicles and plasma membrane; and two soluble proteins, NSF and SNAP, which catalyze the disassembly of the SNAP-25-syntaxin-synaptobrevin complex during docking and fusion (28). SNAP-25, in association with syntaxin, binds to and modulates voltage-gated calcium channels, thus bringing the vesicle into close proximity with a source of calcium. Both N-type and P/Q-type calcium channels have been implicated in neuronal exocytosis, with synaptotagmin I acting as a low-affinity calcium sensor (29).

The critical role of calcium in exocytosis, termed the "stimulus-secretion coupling" hypothesis, has been long recognized. Calcium is central to all aspects of exocytosis, including rapid fusion and unloading of the vesicles as well as recruitment and translocation of loaded vesicles. Resting levels of cytoplasmic calcium within the neuron are approximately 0.1 µM and can rise to 5–10 µM upon arrival of action potentials (19). Calcium influx occurs through voltage-gated calcium channels and leads to fusion of the synaptic vesicles with the plasma membrane and release of their content to the extracellular space. This is a much faster process than the relatively slow release of peptide or protein hormones from endocrine cells.

In most neurons, dopamine is released into the synaptic cleft and binds to postsynaptic receptors. In contrast, the dopaminergic neurons of the hypothalamo-pituitary unit (with the exception of the dopaminergic neurons innervating the intermediate lobe of the pituitary) lack true synaptic contacts and are classified as secretory neurons (30). In this case, dopamine diffuses away from the terminals through the perivascular space and is transported by portal blood to distal pituitary target cells. The rate of dopamine release from secretory neurons appears to be slower than that from classical neurons. It has been argued that the speed of neurotransmitter release is reciprocally related to the distance of its site of action, but the mechanism responsible for this feature is unclear (19).

Calcium influx in chromaffin cells induces an initial fast release, termed the "exocytotic burst," which occurs in milliseconds and is followed by a slower and sustained release phase that lasts several seconds (27). It is assumed that only a small fraction of docked vesicles can instantaneously release their cargo in response to calcium influx. These vesicles comprise the "fusion-ready" pool that undergoes a very rapid ATP-dependent fusion. The slower release phase is carried out by docked vesicles that exist in a different biochemical state and require priming to promote fusion. These vesicles constitute a precursor pool that replenishes the rapid release pool. Priming is ATP dependent, involves the SNARE proteins, and is associated with production of phosphoinositides and protein phosphorylation. An even slower pool is composed of vesicles that are anchored to the cytoskeleton via actin-binding synapsins but are not docked to the membrane (25). When synapsins become phosphorylated in response to an influx of calcium, the vesicles detach from the cytoskeletal elements and can translocate to the active zone of the presynaptic membrane. However, vesicular translocation is too slow to account for the immediate calcium-dependent exocytosis.

Norepinephrine is released from chromaffin granules together with ATP and chromogranins but it is unclear whether this also occurs in dopaminergic neurons (23). The dynamics of release has been studied by electrophysiological approaches capable of resolving single exocytotic events. Such techniques can detect small changes in membrane capacity, reflecting an increase in plasma membrane surface due to vesicular fusion, and can also measure the oxidation/reduction potential of minute amounts of the released transmitter (31). Two pathways have been proposed to explain formation of fusion pores that connect the vesicle lumen with the extracellular space. One is termed the "kiss-and-run pathway," in which a pore is formed to allow partial or full emptying of the vesicle content. The other is termed the "complete fusion pathway," in which the pore dilates and the vesicle membrane collapses into the plasma membrane (18, 32). At least two membrane proteins, synaptophysin and synaptoporin, have been associated with pore formation. Questions that remain to be resolved include the three- dimensional structure of the putative pores, the precise mechanism of vesicular retrieval, and the dynamic forces that drive intracellular trafficking of the internalized vesicles.

C. Transporters
Reuptake is the process by which the released transmitter is brought back into presynaptic nerve terminals or is internalized by surrounding glial cells. It is unique to monoamines and amino acid neurotransmitters and is the main mechanism by which the action of the released transmitter is rapidly terminated (see Fig. 1). As an added benefit for monoamines, reuptake permits recycling of the same molecules while saving in energy costs of their biosynthesis (33). In contrast, the action of the released neuropeptide is terminated either by diffusion or by proteolysis.

Reuptake of dopamine is mediated by two classes of transporters: dopamine transporter (DAT), which transports dopamine from the extracellular to the intracellular space, and VMAT, which reloads dopamine into the vesicles (reviewed in Ref. 34). The two transporters differ in structure, cellular localization, substrate specificity, antagonist selectivity, and energy requirements (for a schematic presentation of the two transporters, see Fig. 2). Because dopamine in the hypothalamo-pituitary axis is not released directly into synapses, it has been argued that reuptake is not physiologically important in these neurons (35). As discussed in more detail in Section III.B, compelling evidence now indicates that a dopamine reuptake mechanism, though not robust, is an essential component in the overall regulation of PRL homeostasis.

View larger version (41K): [in this window] [in a new window]   Figure 2. Comparison of the structures of dopamine receptors (upper panel) and transporters (lower panel). Receptors: Both D1Rs and D2Rs belong to the superfamily of 7 TMDs, G protein-coupled receptors. D2Rs have a larger third intracellular loop, whereas D1Rs have a longer cytoplasmic carboxyl terminus. The locations of N-glycosylation (open circles), putative phosphorylation (circles with embedded P) sites, the s-s bridge in the extracellular face, and site of palmitoylation in the cytoplasmic face are also shown. Transporters: Both DAT and VMAT have 12 TMDs but otherwise have little primary sequence homology. Unlike the receptors, both the N- and C-termini of the transporters are located at the cytoplasmic side of the membrane. DAT has a large, N-glycosylated extracellular loop between TMDs 3 and 4, whereas the largest intraluminal loop of VMAT is located between TMDs 1 and 2. Open circles designate glycosylation sites.

The -aminobutyric acid (GABA) transporter (GAT) was the first neuronal transporter isolated by classical protein purification methods, followed by cloning of the norepinephrine transporter, NET (reviewed in Refs. 36 , 37 , and 40). After screening cDNA libraries from the rat midbrain with oligonucleotide probes complementary to conserved regions of these transporters, DAT was cloned by three groups in 1991 (41, 42, 43). Many neuronal transporters have since been cloned and are now grouped into a large family characterized by multiple transmembrane domains (TMDs) and sodium dependence. DAT belongs to a subfamily that includes transporters for GABA, norepinephrine, serotonin, glycine, and proline and is distinguished by 12 TMDs and dependence on both Na⁺ and Cl^-. Another subfamily is chloride independent, has 6–9 TMDs, and includes transporters for the excitatory amino acids glutamate and aspartate (40).

The DAT gene in humans is mapped to chromosome 5p (44). It spans 64 kb and is made of 15 exons, with the coding region beginning in exon 2 and extending partially into exon 15. There is a close correspondence between the exons and the putative TMDs, with no evidence for multiple start or polyadenylation sites or alternative splicing. The proximal 5'-flanking sequences lack canonical TATA or CAAT boxes and contain only a few known response elements for transcription factors (45). More distal sequences have multiple binding sites for nurr1, an orphan nuclear receptor transcription factor that is critical for the development of midbrain dopaminergic neurons (46), although it is not expressed in the hypothalamic dopaminergic neurons (47). A combination of positive and silencing elements within the promoter region accounts for the selective cellular localization of DAT within the brain. Although a number of potential transcription factor response elements (Erg-1, E-box, AP-2) have been identified in the proximal DAT promoter, their precise role in the regulation of DAT gene expression has not been well defined (45).

DAT encodes a 69-kDa protein of 620 residues with both the N and C termini located intracellularly (reviewed in Ref. 48 ; see Fig. 2). The protein lacks a consensus signal sequence and has 3–4 potential N-linked glycosylation sites in the second large extracellular loop. The nature and extent of glycosylation are tissue specific and may be involved in transporter targeting, stability, or ligand binding. Residues within TMD 1–3 influence binding affinity for dopamine and cocaine, whereas those in TMD 11–12 affect the affinity for the 1-methyl-4-phenylpyridinium ion (MPP⁺) neurotoxin (49, 50). As is typical for all neuronal transporters, DAT has lower affinity and reduced ligand specificity than the dopamine receptor. Several potential sites can be phosphorylated by PKC and may determine the rate of uptake or serve as a signal for transporter internalization (51).

As revealed by combined in situ hybridization and immunocytochemistry, DAT has restricted localization within the brain and is not expressed outside the CNS (34). The transporter colocalizes with TH, and because it is limited to dopaminergic neurons, it serves as a unique marker for these neurons. The highest expression of DAT is in the substantia nigra, followed by the ventral tegmental area. DAT in these neurons is detected in perikarya, dendrites, and axonal processes. A significant presence of DAT is also seen in mesolimbic and mesocortical dopaminergic pathways (52), whereas the hypothalamic dopaminergic neurons exhibit moderate and restricted expression of DAT. Unexpectedly, electron microscopy reveals that the DAT protein is found primarily in the extrasynaptic area rather than in the active zone of the synapse (53). This suggests that DAT may play a role in limiting diffusion of dopamine after being released. An unresolved issue is the mechanism by which dopamine ((nd other monoamines) is taken up by glia, because DAT is undetectable in these cells.

DAT is targeted by psychostimulants such as cocaine and amphetamine. By binding to the transporter and preventing dopamine reuptake, these drugs cause a prolonged increase in extracellular dopamine, resulting in augmentation of its effects. Because DAT is an excellent marker for functional extrahypothalamic dopaminergic neurons, in vivo imaging of cocaine analogs is used to evaluate the state of dopaminergic neurons in patients with Parkinson’s disease and other neurological disorders (54). The generation of transgenic mice with DAT inactivation added significant information on the physiological role of this transporter. These mice are hyperactive, do not respond to cocaine or amphetamine, are resistant to the neurotoxic effects of MPP⁺, and their dopamine receptor expression is down-regulated (55). The state of PRL and other hormones of the hypothalamo-pituitary axis in such animals is covered in detail in Section V.A.

Two VMAT isoforms, VMAT1 and VMAT2, were identified by expression cloning. They arise from distinct but related genes that encode proteins of 520 residues (reviewed in Refs. 33 and 56). Although they also have 12 putative TMDs, there is no sequence homology with the membrane transporters. The vesicular transporters are characterized by a large hydrophilic N-glycosylated intraluminal loop between TMDs 1 and 2, with both C and N termini located on the cytoplasmic side of the vesicular membrane (see Fig. 2). VMAT1 is present in developing neurons, peripheral tissues, and in some endocrine cells. VMAT2 is expressed in all major monoaminergic neurons throughout the brain, with a broad specificity for monoamine transport rated as serotonin> dopamine>norepinephrine>epinephrine>histamine (34). The weak substrate specificity indicates that uptake and storage of a secreted transmitter by the appropriate neuron is determined by the cell-selective plasma membrane transporter rather than by the vesicular transporter. Unlike DAT-deficient mice, which survive into adulthood, deletion of VMAT2 results in early postnatal mortality, underscoring the obligatory role of vesicular storage of monoamines for survival (57, 58, 59).

VMAT recharges the vesicles with the neurotransmitter by using an electrochemical gradient generated by vacuolar ATP-dependent H⁺ pump (V-ATPase). This pump maintains an intravesicular acidic environment (pH of 5.5 in chromaffin granules), which is necessary for uptake of the transmitter against its concentration gradient (60). Hence, VMAT differs from DAT and other membrane transporters that are driven by a Na⁺ gradient. Uptake into the vesicle involves extrusion of two protons for each transmitter molecule that is taken in. The low pH also facilitates packaging/storage of the vesicular content, but it is unclear whether vesicular alkalinization plays a role in exocytosis. In contrast to cocaine and amphetamine, which inhibit dopamine uptake by binding to DAT, the antihypertensive drugs reserpine and tetrabenazine inhibit uptake by interacting with VMAT (61).

D. Receptors
Studies in the late 1970s revealed binding of labeled dopamine to two receptors that were distinguished by pharmacological, physiological, and biochemical criteria and became known as D₁ and D₂ (62). It was then recognized that the D₁ receptor (D₁R) was coupled to G_s proteins and increased intracellular cAMP levels, whereas the D₂ receptor (D₂R) interacted with G_i proteins and inhibited cAMP accumulation. The D₂R was cloned 10 yr later by adopting a cloning strategy based on sequence homology to known G protein-coupled receptors (63). Cloning of the D₁R by several groups followed (reviewed in Ref. 64). Expression of the D₁R and D₂R in host cells confirmed their specificity for the various pharmacological agents and contrasting effects on adenylyl cyclase activity. Since then, three additional dopamine receptors were cloned and characterized. At present, there are 5 distinct receptors that are grouped into two subfamilies: the D1-like family, which includes D₁ and D₅, and the D2-like family, which includes D₂, D₃, and D₄. Because the regulation of PRL by dopamine is mediated by the D₂R, its properties will be emphasized (for structural comparison of D₁R and D₂R, see Fig. 2).

The dopamine receptors are members of the superfamily of G protein-coupled receptors. They are made of single polypeptide chains that range in size from 387 to 475 residues. The receptors have 7 transmembrane (TM)-spanning helices that form a ring-like hydrophobic pocket surrounded by 3 intracellular and 3 extracellular loops. The extracellular amino terminus in all dopamine receptors contains a similar number of residues but has a variable number of N-glycosylation sites (reviewed in Refs. 64 and 65). The cytoplasmic carboxyl terminus is much longer in D₁-like receptors and is the site of receptor anchorage to the plasma membrane via palmitoylation of a conserved cysteine residue (66). The third intracellular loop (between TMs 5 and 6) is significantly larger in the D₂ subfamily, as is the case for most receptors that interact with G_i proteins (Fig. 2). Several phosphorylation sites on the third intracellular loop and the cytoplasmic tail participate in receptor desensitization, although the physiological importance of desensitization is best established for adrenergic receptors (67). Two cysteine residues on the second and third extracellular loops form a disulfide bond that stabilizes receptor conformation. A combination of site-directed mutagenesis and protein modeling suggests that conserved amino acids in TM 2 ((spartate), TM 3 ((spartate), TM 5 (two serines), and TM 6 (phenylalanine) define a narrow pocket for agonist binding (64, 68).

The five dopamine receptors have different chromosomal localization, i.e., 5q, 11q, 3q, 11p, and 4p for D₁, D₂, D₃, D₄, and D₅, respectively (69). It has been proposed that most of the genes encoding G protein-coupled receptors originated from a primordial gene, probably one of the opsin genes (70). The genomic organization of the dopamine receptors is consistent with their divergence from two gene subfamilies that differ in the presence or absence of introns. Like most G protein-coupled receptors, the D₁-like receptor genes have no introns, whereas the D₂, D₃, and D₄ receptors have 6, 5, and 3 introns, respectively (71). The presence of introns permits generation of receptor variants by alternative splicing. D₂R has two functional variants, a short isoform, and a long isoform having a 29-residue insertion in the third cytoplasmic loop (72). Expression, regulation, and signaling of these variants within the anterior pituitary are covered in Section IV.A. Splice variants of other dopamine receptors may generate nonfunctional proteins.

In general, the D₁ and D₂ receptors are expressed at higher levels and have more selective agonists and antagonists than the D₃, D₄, and D₅ receptors (reviewed in Ref. 64). The five receptors have distinct, though often overlapping, localization within the brain and are expressed in a tissue-specific manner in the periphery. D₂R mRNA is highly expressed in the substantia nigra, ventral tegmental area, and hippocampus, whereas the amygdala contains primarily D₁ with only little D₂ mRNA. Both receptors are expressed at high levels in the caudate putamen, nucleus accumbens, and olfactory tubercle (73). The hypothalamus has moderate levels of both D₁ and D₂ mRNAs and low levels of D₄ and D₅. D₂R mRNA is expressed at high levels in both the anterior and intermediate lobes of the pituitary and at lower levels in the adrenal and retina. The D₃ receptor mRNA is not detected in peripheral tissues, whereas a low expression of D₁ and D₄ in the kidney and D₅ in the heart has been reported (74).

The association of dopamine receptors with many neurological disorders has led to the development of many agonists and antagonists (reviewed in Ref. 75). While the availability of stereoselective drugs was instrumental in the initial characterization of the receptors, their cloning subsequently helped in the discovery of more selective drugs. Dopamine receptor antagonists are known as neuroleptics and are widely prescribed for the treatment of schizophrenia and other psychoses (76). Because many neuroleptics elicit Parkinsonian side effects, i.e., rigidity and akinesia, it led to the development of newer drugs, known as atypical neuroleptics, with little or no adverse effects on motor functions (77). The most common antagonists of D₂R are (+)butaclamol, chloropromazine, haloperidol, spiperone, sulpiride, and raclopride whereas apomorphine, bromocriptine, pergolide, and cabergolide are potent D₂R agonists (reviewed in Ref. 64). As discussed in Section VI.B, the latter compounds are very effective in the treatment of prolactinomas. Neither of the above-mentioned drugs is absolutely specific for any dopamine receptor subtype, and their selectivity is based on differences in binding affinity and dissociation constants to the various receptors. Thus far, there are no drugs that discriminate between the two D₂R variants.

Signal transduction by the dopamine receptors is an active area of research (reviewed in Refs. 78 and 79). As mentioned before, early studies using brain and pituitary tissues established that activation of D₁-type receptors increased adenylyl cyclase activity, whereas activation of the D₂-type receptors resulted in its inhibition. Because of receptor heterogeneity in brain neurons and lack of truly selective agonists and antagonists, transfection of non-neuronal cells with the various receptors has provided the bulk of information on receptor signaling. The major caveat is that many transfected host cells do not express the G proteins or downstream effectors that are physiologically relevant to receptors on neurons, often leading to conflicting results.

The ability of dopamine receptors to couple to appropriate G proteins is at the heart of their action. It is now recognized that a given receptor can be associated with more than one G protein, thus increasing its diversity of action. The D₁-like and D₂-like receptors are primarily associated with the G_s and G_i subunits, respectively. However, the G₀ and G_q proteins, which are associated with ion channels and phosphoinositide metabolism, are also involved (80). Many of the actions of dopamine receptors are extremely fast, involving rapid changes in ion fluxes across the cell membrane. In some target cells, including the pituitary lactotrophs, receptor activation also leads to changes in gene expression and hormone secretion as well as alterations in cell growth and differentiation. The signal transduction pathways of the pituitary D₂R and their multiple effects on the lactotrophs are covered in Sections IV.A and IV.B.

In contrast to the aforementioned receptors that are localized post synaptically, dopamine autoreceptors are found on most parts of the neuron, i.e., soma, dendrites, and terminals (81, 82). Autoreceptors are divided into three subcategories that are classified by their ability to modulate dopamine synthesis, release, or neuronal firing rates. After being released from the neuron, dopamine can interact with autoreceptors and inhibits further release of the neurotransmitter. The elevated intracellular dopamine also suppresses TH activity by binding to its pterin cofactor and decreasing the rate of synthesis. Some prefrontal neurons, as well as the hypothalamic dopaminergic neurons, lack synthesis-modulating autoreceptors (83). Although both D₂ and D₃ receptors have been proposed to function as autoreceptors, the issue remains controversial. It is also unclear whether distinct receptor proteins modulate each of these functions or the same receptor protein is coupled to each function through distinct transduction mechanisms.

	III. The Hypothalamo-Pituitary Dopaminergic Systems

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
A. Anatomy and ontogeny
The brain contains several well-defined dopaminergic systems. The most extensively studied are the nigrostriatal, mesolimbic, and mesocortical neuronal systems that originate in the midbrain and project to the striatum, limbic system, and cortex, respectively. These are involved in the control of locomotion, emotion, and cognition and have no direct role in the regulation of pituitary function. Within the hypothalamus, dopamine perikarya are located in several sites that are classified by the alphanumeric system of Dahlstrom and Fuxe (84). These include the posterior hypothalamus ((11), arcuate nucleus ((12), zona incerta ((13), periventricular nucleus ((14), and lateral and ventral hypothalamus ((15). Neurons arising from the A11 locus send axons to the spinal cord and constitute a diencephalospinal system whose function is not well understood. The incertohypothalamic neurons from the A13 group project diffusely to different areas of the hypothalamus and participate in the control of GnRH release. They also send some projections to more remote areas such as the amygdala. Although not well characterized, the neurons originating from A11 and A13 regions constitute the majority of the hypothalamic dopaminergic neurons (for review, see Ref. 14). Only neurons originating from the A12 and A14 groups are relevant to our discussion because they are directly involved in the control of PRL secretion.

Based on anatomical and functional studies, two dopaminergic systems that regulate PRL were initially identified: the tuberoinfundibular dopaminergic (TIDA) and tuberohypophysial dopaminergic (THDA). Further refinements in neuronal tracing techniques (85) revealed that most of the THDA neurons projecting to the neurointermediate lobe actually originate from the A14 cells in the periventricular nucleus and therefore were termed the periventricular- hypophysial dopaminergic (PHDA) system (86). Because of their lower abundance and heterogeneous distribution, the hypothalamic dopaminergic neurons are not as well characterized as their nigrostriatal counterparts.

The TIDA neurons provide the major dopaminergic input to the anterior pituitary (see Fig. 3). Most of their perikarya are located in the dorsomedial part of the arcuate nucleus, with a smaller population arising from the periventricular nucleus. Their relatively short axons terminate in the external zone of the median eminence near the primary capillary loops of the hypophysial portal vessels (reviewed in Ref. 14). The median eminence contains a negligible number of cell bodies and a dearth of classical synapses. Instead, the TIDA system represents neurosecretory neurons whose product is released into perivascular spaces surrounding the capillary loops and is carried by the portal blood to the anterior pituitary. Notably, some TH-positive perikarya in the ventrolateral portion of the arcuate nucleus that also project to the median eminence do not express DDC (87) or DAT (88) and are believed to release DOPA rather than dopamine. Because DOPA has not been detected in hypophysial portal blood, the DOPA that may be released from these neurons must be decarboxylated before reaching the pituitary. Whereas the arcuate nucleus receives multiple afferent connections from VIPergic, opioidergic, serotonergic, and NPYergic neurons among others, their precise connections to TH-positive neurons needs further clarification.

View larger version (28K): [in this window] [in a new window]   Figure 3. Diagram of the hypothalamic dopaminergic systems that regulate PRL. The TIDA neurons originate in the A12 region of the dorsomedial arcuate nucleus. They have short axons that terminate in the external zone of the median eminence near the primary capillary plexus of the portal vessels. The released dopamine is carried out by the long portal vessels to the anterior lobe ((L) of the pituitary. The THDA/PHDA neurons have perikarya primarily in the A14 region of the periventricular nucleus and send projections to the neural (NL) and intermediate (IL) lobes of the pituitary. The short portal vessels connect between the NL and AL but bypass the IL which is avascular. [Derived from M. E. Freeman et al.: Physiol Rev 80:1523:1631, 2000 (105 )].

The anatomy of dopaminergic neurons in the human hypothalamus has not been well characterized (reviewed in Ref. 14). Undoubtedly, dopamine is important for the regulation of PRL release in humans because drugs that interfere with its release or action affect circulating PRL levels to the same extent as they do in experimental animals. However, there is no clear demarcation of the A11–A14 dopaminergic groups in humans, and most TH-positive, DBH-negative neurons (designating dopaminergic rather than noradrenergic neurons) reside in the magnocellular neurons (91). However, it is clear that the hypothalamic dopaminergic neurons in humans have distinct properties from those in the nigrostriatal region, and their normal function is preserved in Parkinson’s disease. Indeed, Parkinson’s patients do not have elevated plasma PRL levels, and their basal PRL release is suppressed by dopaminergic agonists (92). Another point of departure from rodents is the absence of a distinct intermediate lobe in adult humans ((s opposed to its discrete presence in fetuses) and no comparable PHDA system. Although melanotrophs are sparsely distributed throughout the human pituitary, they are neither innervated by dopaminergic neurons nor respond to dopamine agonists and antagonists (93).

Embryonic development of the hypothalamic dopaminergic neurons in the rat progresses along four chronological stages: 1) generation from neuroepithelial precursors, 2) expression of biosynthetic enzymes, production of dopamine, and establishment of mechanisms for its reuptake and release, 3) development of efferent connections, and 4) formation of afferent innervation and synaptogenesis (for review, see Ref. 94). Stage 1 neurons are first detected in the zona incerta and periventricular zone on embryonic days (ED) 12–13, followed by those in the arcuate nucleus on ED 14–15. On ED 17–18, TH-immunoreactive neurons (95) and TH mRNA (96) are detectable throughout the hypothalamus, with TH-positive axons appearing in the median eminence 2 d later. Expression of TH, however, does not imply terminal neuronal maturity. In fact, the high levels of DOPA in the fetal hypothalamus (97) and in conditioned media from cultured fetal hypothalamic neurons (98) suggest low activity of DDC and diminished ability for dopamine biosynthesis.

Stage 2 neurons expressing both TH and DDC and capable of release and reuptake of dopamine first become apparent on ED 15–16 (99). Sexual dimorphism of arcuate neurons is already evident at this time, with number of TH-positive neurons higher in males but their size and content higher in females (99). The gender difference in dopamine content is maintained during culture of fetal diencephalic neurons, which respond to chronic exposure to gonadal steroids by decreased rate of DOPA synthesis in cultures from both sexes (100).

The development of the THDA/PHDA system is delayed. TH-positive fibers are first seen in the neural lobe on ED 20 and in the intermediate lobe 3–4 d after birth (95, 101). Intermediate lobe-derived factors such as brain-derived neurotropic factor and neurotropin-3 may be involved in directing outgrowth of the dopaminergic neurons from the hypothalamus toward the pituitary (102, 103). The density of TH immunoreactivity in the intermediate lobe increases during the 1st wk of life, with dopamine reaching peak concentrations by the end of the 2nd wk and decreasing thereafter (104). The increased density of dopaminergic innervation in the intermediate lobe during early postnatal life correlates with the ontogeny of dopamine binding sites and coincides with a marked reduction in the number of melanotrophs (104), reflecting the inhibitory action of dopamine on melanotroph proliferation.

B. Physiology and pharmacology
Of the three dopaminergic systems, the TIDA neurons play the predominant role in the control of PRL release. Substantial evidence, based on the measurement of dopamine in portal blood and determination of its concentration and turnover rates in both the arcuate nucleus and median eminence, has established that the activity of the TIDA neurons is altered under many physiological conditions known to affect PRL release (reviewed in Refs. 1 and 105). However, the early notion that the TIDA neuronal activity must be negatively correlated with PRL release is too simplistic because the expected reciprocal relationship between dopamine and PRL is often masked by the action of other factors, both positive and negative, that control PRL release.

The lactotroph is unique among endocrine cells in having a high basal secretory activity. Tonic inhibition by dopamine, which maintains low circulating PRL levels, requires a continuous high input of dopamine. The high output, in turn, depends upon a sustainable high rate of synthesis. To enable rapid PRL surges, the dopaminergic input to the lactotrophs must be concomitantly decreased. This process is accomplished by a unique mechanism governing the regulation of hypothalamic TH activity. TH in most tissues exists in a quiescent, nonphosphorylated state. In response to stimuli, the enzyme is rapidly phosphorylated, resulting in increased hydroxylation of tyrosine to DOPA and its instant conversion to dopamine that is immediately available for release (9). One notable exception is hypothalamic TH. In keeping with the constant demand for high dopamine output, hypothalamic TH is constitutively active, as judged by its lower Michaelis-Menten constant (K_m) for the pterin cofactor than striatal TH (106). In response to estrogen, hypothalamic TH is transiently inactivated, presumably by dephosphorylation because this can be reversed by inhibitors of protein phosphatases such as okadaic acid (107). This is supported by the report on rapid decline in TH activity in hypothalamic slices within 1 h of E2 treatment (108). The absence of dopamine autoreceptors on the TIDA neurons may assist in maintaining high dopamine output by reducing, or eliminating, the negative feedback by dopamine on TH activity.

As discussed before, reuptake plays a fundamental role in neuronal function by conserving the released neurotransmitter and terminating its synaptic action. Because the hypothalamic neurons release dopamine into portal blood rather than into synapses, early reports suggested that that the hypothalamic dopaminergic neurons lack a functional reuptake mechanism (35, 109). This was refuted by a later study demonstrating dopamine reuptake by incubated stalk median eminence and posterior pituitary, with reuptake inhibitors such as nomifensin and diclofensin increasing media dopamine levels after neuronal depolarization (110). The molecular basis for this reuptake process was later confirmed by the detection of DAT mRNA in the dorsomedial arcuate nucleus (34) and the demonstration of immunoreactive DAT in the median eminence, pituitary stalk, and intermediate and neuronal lobes (111).

The physiological relevance of this reuptake was supported by the acute suppression of serum PRL levels in ovariectomized (OVEX) rats treated with competitive DAT inhibitors such as cocaine or mazindol (111). Moreover, DAT-knockout mice, presumably because of increased dopamine outflow, have a marked reduction in pituitary PRL content and do not lactate (112). Since the ratio of DOPAC/dopamine in the median eminence is less than half that in the striatum (113), most of the released dopamine must be carried away by the portal blood and lesser amounts are taken up by the terminals and converted to DOPAC.

Although males and females have the same density of TIDA nerve terminals, there are marked sexual differences in their activity and responsiveness to physiological and pharmacological stimuli. Basal TIDA neuronal activity is higher in females, is decreased by ovariectomy, and is restored by estrogen (for review, see Refs. 105 and 113). An opposite trend is seen in males, whereby TIDA activity increases by orchidectomy and decreases by T. The lower basal activity of these neurons in males may be due to tonic inhibition by endogenous opioids (114). The TIDA neurons in females are more sensitive to stress and to feedback stimulation by PRL but less sensitive to bombesin and -opioid antagonists (115, 116).

The TIDA neurons also exhibit an endogenous daily rhythm of activity (for review, see Ref. 105). This is controlled by the suprachiasmatic nucleus (SCN), which coordinates photoperiodicity in the neuroendocrine axis. A proestrous-like mid-afternoon PRL surge can be induced daily in OVEX rats by estrogen, implicating some form of coupling to an intrinsic diurnal rhythm. TIDA neuronal activity in the estrogen-treated OVEX rats is high in the morning, decreases before the PRL surge, but remains suppressed throughout late afternoon (117, 118). Although these changes correlate well with the initiation of the surge, they do not correspond to its termination, suggesting involvement of factors other than dopamine. Progesterone also participates in the control of the TIDA rhythm by advancing the afternoon decline in TIDA activity (119). Such rhythmic activity does not occur in males and is abolished in females by lesions of the SCN (113). These data suggest that activation/inactivation of the TIDA neurons is driven by an endogenous rhythm that is independent of the reproductive state, but its amplitude and timing are modulated by ovarian steroids. Several factors, including opioid peptides, bombesin, and acetylcholine (113), whose actions may be mediated by nitric oxide (120), have been implicated in the control of the endogenous dopaminergic rhythm. The relative importance of all these factors as well as the hierarchy of their action remain to be defined.

The role of the THDA/PHDA neurons in PRL regulation has been controversial. Early studies failed to show a good correlation between THDA neuronal activity and PRL release, suggesting that they do not contribute to the control of PRL secretion (116). Other investigators, however, found that the concentrations of dopamine and DOPAC in the intermediate lobe exhibit a daily rhythm with a significant decline that coincides with the initiation of the proestrous PRL surge (121). They also found alterations in the DOPAC/dopamine ratio in both the intermediate and neural lobes in response to ovarian steroids (122) and PRL (123), indicating that all three populations of the dopaminergic neurons are involved with PRL homeostasis.

Unlike the long portal vessels that connect the median eminence to the anterior pituitary and can be cannulated, the short portal vessels linking the neural and anterior lobes are inaccessible for sampling. Therefore, the relative contribution of the THDA/PHDA neurons to the total dopamine reaching the anterior pituitary cannot be effectively determined and requires indirect approaches. Surgical removal of the posterior pituitary (posterior pituitary lobectomy or LOBEX) provided the first evidence that dopamine from the THDA/PHDA neurons suppresses PRL release. LOBEX in either male or female rats caused an increase in serum PRL levels, but not LH or GH, which was reversed by intracarotid injections of dopamine (124, 125). Another indirect method is compression of the pituitary stalk, which disrupts the neural input to the neurointermediate lobe but does not impede the blood supply to the pituitary (126). Within 1 wk of denervation, circulating PRL and -MSH levels increased 3- to 4-fold, whereas those of LH remained unchanged. The mode of transport of dopamine from the avascular intermediate lobe to the anterior lobe remains enigmatic. One possibility is that it diffuses into the vicinity of lactotrophs that line the pituitary cleft. Another possibility is that intermediate lobe dopamine indirectly regulates PRL by suppressing the release of a local PRL releasing/regulating factor (reviewed in Ref. 127).

The pharmacology of the hypothalamic dopaminergic neurons has been the subject of several studies. These revealed that the responsiveness of the TIDA neurons to dopaminergic agents differs in several respects from their striatal counterparts. Because the TIDA neurons lack autoreceptors, they are unresponsive to acute administration of nonselective dopamine agonists, such as apomorphine, which do not discriminate between D₁-like and D₂-like receptors (128). Such drugs, therefore, act indirectly by altering the secretion of PRL, which in turns affects the TIDA neurons via a short loop feedback mechanism.

Classical antipsychotic drugs with D₂R antagonistic properties, such as haloperidol, have no direct effect on the TIDA neurons but induce their activation within several hours, secondary to the rise in circulating PRL levels (129). On the other hand, atypical neuroleptics such as clozapine acutely increase TIDA neuronal activity, possibly by activating D₁Rs. Acute administration of D₁ agonists (e.g., SKF 38393) inhibits, whereas D₂ agonists (e.g., quinpirole) stimulate, the TIDA neurons. The opposing effects of stimulatory D₂Rs and inhibitory D₁Rs likely account for the lack of net effect of mixed D₁R/D₂R agonists on the TIDA neurons (128). In males, some of the D₂R-mediated activation of the TIDA neurons occurs via disinhibition of afferent dynorphinergic neurons that provide tonic inhibition over the TIDA neurons (130).

C. Regulation by PRL
In the absence of target gland hormones to provide feedback control over the lactotrophs, PRL regulates its own release by acting on the hypothalamic dopaminergic systems. This type of interaction, termed "short loop feedback," is mostly responsible for the maintenance of PRL homeostasis. Many studies have established that an increase in either endogenous or exogenous PRL results in higher activity of the TIDA neurons, whereas a decrease in circulating PRL levels, resulting from hypophysectomy, immunoneutralization, or dopamine agonists, lowers their activity (reviewed in Refs. 1 , 105 , and 131). The TIDA neurons respond to both acute and chronic changes in PRL with few exceptions. The latter include pregnancy, lactation, and prolactinomas, when the dopaminergic neurons become refractory to the elevated PRL levels, thereby upholding physiological or pathological hyperprolactinemia.

The existence of a short loop feedback arrangement between PRL and dopamine raises several questions: Are the effects of PRL direct or indirect, and if indirect, what are the mediators? How does PRL gain access to the TIDA neurons? What are the nature and cellular distribution of hypothalamic PRL-Rs, and how are they regulated? Are both the TIDA and THDA/PHDA systems regulated by PRL? And finally, which functions of the dopaminergic neurons are affected by PRL? Presently, there are only partial answers to these questions.

The issue of direct vs. indirect effects of PRL on the TIDA neurons is difficult to resolve, given the scarcity of suitable in vitro systems. A direct effect is suggested by the increase in TH activity in cultured fetal hypothalamic neurons incubated with PRL (98). Although most of the TH-expressing neurons were immunopositive for the PRL-R, they constituted less than 10% of the total cell population in these cultures, and the receptors were also expressed by 20–25% of other neurons. In another study, dopamine concentration in TIDA neurons increased within 1 h after injecting ovine PRL to OVEX rats, indicating very rapid activation (123); a second delayed increase in dopamine turnover was seen in both the intermediate and neural lobes. Rapid activation by PRL of immediate early genes such as Fos-related antigens (132) and nerve growth factor (NGF)1-A (133) in TH-positive neurons in the arcuate nucleus also demonstrates PRL autofeedback. Neither study, however, conclusively established a direct effect of PRL, and mediation by substances such as neurotensin, NPY, and opioids cannot be ruled out.

Circulating proteins are excluded from the brain proper except for the circumventricular organs, e.g., the median eminence and neural lobe, which are outside the blood brain barrier. Given the location of the arcuate nucleus within the medial basal hypothalamus, it raises the question of how PRL reaches the TIDA neurons. PRL, which is detectable in many hypothalamic and extrahypothalamic sites (134, 135), can be derived from two sources: transport from the circulation, and local synthesis. Transport to the cerebrospinal fluid (CSF) occurs by receptor-mediated PRL uptake at the choroid plexus (136), which has the highest density of PRL-R in the brain (137, 138). The mechanism by which this receptor acts as a transporter is unknown. Upon gaining access to the CSF, PRL can be distributed to various sites, including the arcuate nuclei, which is adjacent to the third ventricle. The hypothalamus is also capable of de novo synthesis of PRL, a process that is regulated by an estrogen-sensitive mechanism (135). Although locally produced PRL may act as a mitogen for astrocytes (139), its participation in the short loop feedback on the TIDA neurons is doubtful.

The PRL-R belongs to the hematopoietic receptor family that includes GH, many cytokines, and some growth factors (for review, see Refs. 140, 141, 142). These are characterized by a single hydrophobic transmembrane domain that divides the receptor into an extracellular ligand binding domain and an intracellular domain. Features common to the extracellular domain include four paired cysteine residues and a wsxws (or WS) motif (tryptophan-serine-any amino acid-tryptophan-serine) that are involved in the formation of a ligand binding pocket. The cytoplasmic domains of the receptors differ in size and structure among the various family members. A hydrophobic proline-rich motif (homology box 1), located near the transmembrane region, is essential for signal transduction of all ligands studied. The PRL-R and several other hematopoietic receptors also contain a less-conserved cytoplasmic region, denoted box 2, whose function is not as well defined (143).

In the rat, alternative splicing generates two PRL-R isoforms, a short isoform of 291 amino acids and a long isoform of 591 amino acids. They have identical extracellular domains but differ in the length and sequence of the intracellular domain (Fig. 4). The promoter of the PRL-R gene belongs to a TATA-less/noninitiator class and has at least three regions that direct transcription from alternative sites in a tissue-specific manner (142). Both long and short receptor isoforms are expressed in most tissues, and their ratio is altered under many conditions (144). Although the exact function of each isoform remains to be fully defined, their coupling to different signal transduction pathways accounts for many of the pleiotropic actions of PRL (143). An "intermediate" form, lacking 198 amino acids due to a deletion, is uniquely expressed by the Nb2 rat T lymphocyte cell line (145) and confers growth dependence on PRL by these cells. A soluble form of the receptor, named PRL binding protein, resulting either from alternative splicing of the transcript or proteolytic cleavage of a membrane-bound receptor protein, has also been detected (146). The human PRL-R is encoded by a single gene that contains at least 10 exons and is located on chromosome 5 in close proximity to the GH receptor gene (147). In addition to the long form, a truncated isoform was identified in human breast cancer cell lines (148).

View larger version (32K): [in this window] [in a new window]   Figure 4. Diagram of the different types of PRL-Rs in the rat. The PRL-R belongs to the hematopoietic receptor family characterized by a single short TMD. The extracellular ligand binding domain has several common features, including two disulfide bonds and WS (Trp-Ser-X-Trp-Ser) motif. A proline-rich homology box 1, located near the transmembrane region, is essential for signal transduction. The long and short isoforms are the products of differential splicing, with the short isoform possessing a distinct C terminus. An intermediate isoform, unique to Nb2 lymphocytes, has a deletion of 198 amino acids. A soluble form of the receptor, termed "PRL binding protein," has also been detected. [Derived from C. Bole-Feysot et al.: Endocr Rev 19:225–268, 1998 (140 ). © The Endocrine Society.]

Unlike many growth factor receptors, the PRL-R has no endogenous kinase activity, using instead the Janus kinase (JAK)-signal transducer and activator of transcription (Stat) pathway as its major signal transduction mechanism (for reviews, see Refs.140 and 155). JAK2, which is constitutively associated with the PRL-R, is phosphorylated upon receptor activation by the ligand. In turn, the activated JAK2 phosphorylates other proteins, including the receptor itself and Stat proteins, e.g., Stat 1, Stat 3, and Stat 5 (( and b isoforms). The phosphorylated Stat proteins dimerize and translocate to the nucleus where they bind to specific DNA motifs, called -interferon-activated sites, in the promoter regions of PRL target genes. Other transduction pathways, including the MAPK cascade and Src kinases, have been implicated in PRL-R signal transduction (reviewed in Ref. 140).

The mRNA of the PRL-R is expressed in practically all tissues with the highest density seen in the liver, choroid plexus, ovary, and mammary gland (144). Next to the choroid plexus, the hypothalamus has the highest density of PRL-R in the brain, with a dissociation constant (K_d) of 0.2–0.3 nM and maximal binding (B_max) of 5–10 fmol/mg proteins (156). Many hypothalamic nuclei, including the rostral arcuate and periventricular nuclei, in which perikarya of the TIDA and PHDA neurons are located, express mRNA and contain immunoreactive PRL-R (157). However, the receptor is expressed only by some, but not all, TH-positive neurons (98, 157). The long isoform is predominant, but both isoforms appear to be regulated under some conditions (158).

The expression of hypothalamic PRL-R mRNA is altered under several physiological conditions without a clear delineation of the specific hormones involved. Expression of the long isoform is increased during proestrus, the second half of pregnancy, and in aged female rats (159, 160, 161). Alterations in circulating PRL levels during lactation (158) and after hypophysectomy (156) increase and decrease, respectively, the hypothalamic PRL-R mRNA levels, suggesting that PRL regulates its own receptors. Similarly, chronic treatment of OVEX rats with estrogens resulted in increased expression of PRL-R mRNA in the TIDA/THDA neurons, paralleling the rise in plasma PRL levels (157). This effect was most pronounced in the dorsomedial and rostral arcuate nuclei and was attenuated by cotreatment with progesterone.

Changes in hypothalamic PRL-R mRNA expression are accompanied by an increased level of receptor protein. For example, immunoreactive PRL-R is higher in the medial preoptic area and periventricular and arcuate nuclei during lactation than in diestrus (162). During lactation, the PRL-R protein becomes detectable in several sites, such as the lateral hypothalamic, supraoptic, paraventricular, suprachiasmatic, and ventromedial nuclei that are undetectable during diestrus. The long isoform is induced in both female and male rats sensitized to pups and exhibiting maternal behaviors (159, 160). In females, receptor induction is dependent on intact ovaries and pituitary because no changes are observed in OVEX or hypophysectomized females when maternal sensitization occurs. In males, this induction is facilitated by PRL administration and is suppressed by cohabitation with females.

TH is one of the targets of PRL action within the hypothalamus, and both short-term enzyme activation (107, 163) and long-term enzyme induction (164, 165) have been observed. PRL immunoneutralization reverses the estrogen-induced increase in dopamine turnover in the median eminence and the intermediate lobe, albeit at different times during the PRL surge (166). In contrast, the observed effect of PRL immunoneutralization on the THDA system is minimal. Another laboratory found that PRL antiserum suppressed basal and haloperidol-induced increases in TIDA activity within 1–2 h, establishing a rapid action of PRL (167). This feedback mechanism is operational in both males and cycling females but is attenuated during late lactation, commensurate with the requirement for prolonged maintenance of elevated PRL levels during this time (168). Chronic hypoprolactinemia and hyperprolactinemia reduce and augment, respectively, TH mRNA levels in the arcuate nucleus but not in the substantia nigra, establishing the site specificity of enzyme induction (107).

PRL also exerts tropic effects on dopaminergic neuronal differentiation, best illustrated in animals with inherited PRL deficiency. Spontaneous mutations of the Snell and Ames dwarf mice result in the absence of lactotrophs, somatotrophs, and thyrotrophs and their respective hormones. The Snell mouse has mutations in the Pit-1 gene (169), a pituitary-specific transcription factor essential for differentiation and maintenance of the three pituitary cell types. The Ames mouse has a mutation in the Prop-1 gene, which normally activates Pit-1, leaving the animals with residual numbers of lactotrophs and somatotrophs (170). Homozygous dwarfs are growth retarded, sterile, and unable to lactate. Dopamine levels are severely depressed in both the TIDA and THDA systems, but not in other brain regions, with no change in norepinephrine (171).

Notably, the TIDA neurons do not differ between dwarfs and normal siblings until d 21 of age. In wild-type mice, dopamine levels and TH-positive neurons continue to increase, whereas those in the dwarfs are unchanged or decline (reviewed in Ref. 172). The dopamine deficiency can be reversed by PRL therapy, but only if initiated at an early postnatal period; adult dwarfs are refractory to PRL. This indicates that PRL acts as a neurotropic factor for the TIDA neurons during a specific developmental window of time. An unresolved issue is whether early postnatal TIDA development is totally independent of PRL or is supported by PRL that is provided by the maternal milk (173).

PRL functions as both a mitogen and survival factor in mammary and immune cells (for review, see Refs. 174, 175, 176), and may have similar functions in the brain. Astrocytes are the most numerous cells in the brain. Unlike neurons, they are capable of proliferation in adulthood. Astrocytes often function as immunocompetent cells and react to brain injury by increased proliferation, cytokine release, and antigen presentation. There is evidence that PRL, but not GH, induces proliferation of growth-arrested astrocytes. The mitogenic effects of PRL require serum-derived factors, suggesting that it functions as a coactivator (139). PRL temporally increases expression of tumor necrosis factor-, IL-1, and TGF- in astrocytes, which in turn may synergize with PRL in promoting astrocyte proliferation and secretory activity (177). The mitogenic/secretory effects of PRL appear to be mediated by the JAK2/Stat pathway, providing the first evidence that PRL signaling within the brain is the same as in peripheral tissues (178, 179). It remains to be determined whether the action of PRL on astrocytes directly or indirectly impinges on the TIDA neurons.

D. Effects of ovarian steroids
Estrogens affect PRL homeostasis at several anatomic sites that include the hypothalamus, posterior pituitary, and anterior pituitary (for review, see Ref. 105). The importance of estrogens in the control of the TIDA neurons is underscored by the higher basal activity of TIDA neurons in females, the suppression of neuronal activity by ovariectomy, and its reversal by estrogen. Some, but not all, of these actions are believed to be mediated by estrogen-induced PRL secretion. Exposure of fetal hypothalamic neuronal cultures to estrogen suppressed basal TH activity and reduced TH mRNA levels, indicating an estrogenic action that is not mediated by PRL (180). On the other hand, in vivo experiments often yield conflicting results because prolonged exposure and high doses of estrogens invariably increase PRL, thereby activating the PRL short loop feedback mechanism. Estrogen alone does not alter TH expression in the arcuate nucleus of monkeys, but causes significant decreases when followed by progesterone (181).

The effects of estrogens are mediated by two receptors, ER and ERß, that are the products of different genes (see Fig. 5). The ER is a member of the ligand-activated nuclear receptor gene superfamily, which includes other steroid receptors, receptors for thyroid hormones, and retinoic acid (for reviews, see Refs. 182, 183, 184). The ER gene is 140-kb long with 8 exons and large introns. The ER protein, composed of 595 amino acids, is divided into five functional domains: a DNA binding domain (DBD), a hormone binding domain (HBD), two transcriptional activation domains [activation function ((F)-1 and AF-2] and a hinge region. The unoccupied receptor is located in the nucleus in an inactive form associated with the molecular chaperone heat shock protein 90. Ligand binding activates the receptor by dissociating heat shock protein 90 and enabling receptor dimerization (185). The HBD is organized in several -helices that form a ligand binding pocket (186), whereas the DBD folds into two dissimilar zinc fingers that interact with an estrogen response element (ERE) on target genes (187). Both domains are required for receptor dimerization.

View larger version (34K): [in this window] [in a new window]   Figure 5. Diagram of ERs. ER and ERß are the products of different genes. The ER transcript is made of 8 exons and encodes a 68-kDa protein, which is divided into several functional domains: AF-1, DBD, hinge region (H), HBD, and AF-2. The pituitary also expresses TERP-1 and TERP-2, both of which are missing the first 4 exons and have unique stretches of 31 bp with an additional 66 bp in TERP-2. ERß is a smaller protein than ER (56–58 kDa) with a 95% homology to ER in the DBD and 55% homology in the HBD but little homology in the AF domains. Several ERß isoforms have also been identified. The different receptors can form either homodimers or heterodimers.

The ERß protein, comprised of 485 amino acids, is smaller than ER (for review, see Refs. 184 and 191). The two receptors share 95% homology in the DBD, 60% in the HBD, but less than 25% in AF-1 (Fig. 5). ERß has a similar binding affinity for E2 to ER, but a higher affinity for the antiestrogen 4-OH-tamoxifen and several xenoestrogens. Splice variants of ERß have insertions or deletions in the HBD that alter the binding affinity of some estrogenic ligands, including xenoestrogens (192). The ERß protein also binds to the consensus ERE and can form either homodimers or heterodimers with ER (193). The tissue distribution of ERß differs from that of ER, with a strong expression in the ovary, prostate, lung, and brain. Within the hypothalamus, ERß expression is especially high in oxytocin- and vasopressin-expressing magnocellular neurons but is only weakly expressed in the dorsal arcuate nucleus (194).

In rat embryos, ERß is detectable in the pituitary anlage as early as ED 12–13, whereas ER becomes detectable only on ED 17 (195). In adult rats, ERß is expressed in most pituitary cell types (195), including lactotrophs (196), but is undetectable in the mouse pituitary (197). The rat pituitary also expresses truncated ER products (TERPs; see Fig. 5), which have not been detected in other tissues (198). Expression of TERPs is up-regulated by estrogens (196), and although they lack DBD, they can dimerize with either ER or ERß, thereby forming inactive dimers that may compete with the wild-type receptors for coactivators (198).

Only a fraction of TH-positive neurons in the arcuate nucleus express ERs with a predominance of ER (199). Similar to PRL, it is unclear whether the estrogenic effect on the TIDA neurons is direct or is mediated by other neurotransmitters or neuropeptides. Many studies have attempted to delineate the temporal effects of ovarian steroids on the dopaminergic neurons throughout the estrous cycles. The low circulating PRL levels observed during most of the cycle rise abruptly on the afternoon of proestrus. Unlike the LH surge, which is sharp and symmetrical, the PRL surge is composed of three distinct phases: an early sharp peak, a prolonged plateau, and a termination phase. Dopamine turnover rates (200, 201) and TH activity (106) are higher during the peak phase than during the plateau, increasing again during the termination phase. Acute ovariectomy on the morning of proestrus prevents the decline in TH activity and mRNA levels (202, 203), with progesterone, but not E2 replacement, restoring TH function. These and several other studies (121, 122, 163) suggest that although a decrease in TIDA neuronal activity contributes to the proestrus PRL surge, PRFs must be involved.

Xenoestrogens are synthetic chemicals with little structural similarity to E2 that can bind to the ER and mimic or interfere with the actions of endogenous estrogens (reviewed in Refs. 204, 205, 206). Whereas most studies focused on the effects of xenoestrogens on the reproductive tracts, several investigators examined their action on the neuroendocrine axis. For example, bisphenol A (BPA), a monomer of polycarbonate plastics and epoxy resins, and octylphenol (OP), a common constituent of detergents and herbicides, increase PRL gene expression and release and induce cell proliferation in cultured lactotrophs (207, 208, 209). Treatment of Fischer 344, but not Sprague Dawley, female rats with moderate doses of BPA resulted in hyperprolactinemia (207); unlike the effect of E2, pituitary weight did not increase. These results suggest genetic predisposition to the action of BPA and its partial agonist activity.

Recently, exposure of newborn male and female rats to either BPA or OP caused a delayed and prolonged hyperprolactinemia and alterations in ER expression in both the hypothalamus and anterior pituitary (210). As shown in Fig. 6, 1 month after treatment of newborn rats with OP, serum PRL levels were elevated, whereas hypothalamic TH activity was markedly suppressed. This suggests that the xenoestrogen caused prolonged down-regulation of TH expression or activity and likely impaired its ability to respond to short loop feedback effect by elevated PRL.

View larger version (24K): [in this window] [in a new window]   Figure 6. Long-term effects of the xenoestrogen OP on PRL release and TH activity. Panel A, Newborn female rats were treated with OP (100 µg/day) or vehicle (control) for the first 5 d of life. On d 30, rats were killed and serum PRL levels were determined by RIA. The dissected stalk median eminence (SME) were incubated for 30 min with NSD-1015, a DDC inhibitor, and DOPA accumulation was determined by HPLC (S. Khurana and N. Ben-Jonathan, unpublished observations). Panel B, Diagram of the relationship between TH activity, dopamine (DA) release, and serum PRL levels under normal conditions. An active TH maintains high DA input, which suppresses PRL release. Panel C, Postulated mode of action of OP at both the hypothalamic and pituitary sites. OP binds to ERs on the lactotrophs and increases PRL secretion; it may also alter the number or activity of lactotrophs. Despite elevated serum PRL levels, there is an ineffective feedback by PRL because DA output is reduced. This could be due to altered expression/activity of TH, down-regulation of the PRL-R on the TIDA neurons, or both.

Cross-talk between estrogen-induced neuropeptide release and endothelial NO has also been reported, showing a rapid increase in GnRH release from the median eminence by BSA-conjugated E2 that cannot pass through the plasma membrane (215). More importantly, this response may be mediated by endothelial-derived NO because it was abolished by NO scavengers and specific eNOS inhibitors. Recently, injection of NO inhibitors or intracerebral administration of NOS antisense oligonucleotides blocked the proestrus PRL surge and partially reversed the decline in TIDA activity, suggesting that NO plays a role on the estrogen-induced changes in dopaminergic neuronal activity (120).

Rapid, nongenomic action of estrogens has also been observed in neurons. An early study reported that 17ß-E2 stimulated dopamine release from depolarized posterior pituitary neurons within 20 min, whereas 17-E2 and T were ineffective (216). Short-term and stereospecific inhibitory effects of E2 on TH activity was later reported using hypothalamic slices (108). E2 also enhanced the amplitude of kainate-induced currents in dispersed hippocampal neurons (217). This effect was also seen in neurons from ER-knockout mice and in the presence of ICI 182,780 (which blocks both ER and ERß), suggesting distinct estrogen binding sites. In both neurons and glia, the fast estrogenic action is often mediated by ERK1/2 phosphorylation via the MAPK signaling pathway (218). Because ERK was activated by BSA-conjugated E2 in the latter study, a membrane ER was implicated.

Recently, rapid (within 5–6 min) induction of PRL release from GH3 cells by a low dose of E2 has been reported (219). In addition, E2 rapidly activates ERK1/2 in pituitary lactotrophs, whereas blocking the MAPK signal transduction pathway ablated the estrogen-induced PRL gene expression (220). The nature of the putative membrane ER is controversial. Although its identity in neurons remains elusive, studies using ER antagonists and antibodies suggest that ER might be the putative membrane receptor in endothelial (221) and GH3 (222) cells. A recent report localized ER in bovine aortic endothelial cells to caveolae (223). Caveolae are pleomorphic membrane microdomains with distinct phospholipid components that are enriched in various receptors and signaling molecules (reviewed in Ref. 224). In both endothelia and cardiac myocytes, eNOS is contained within caveolae and is tonically inhibited by caveolin-1. The localization of ER within caveolae provides a plausible explanation for its sequestration within the plasma membrane and the rapid activation of eNOS. Details of such interactions and how ER might be routed to two distinct compartments, nucleus and caveolae, are yet to be determined.

E. Interactions with neuropeptides and neurotransmitters
In addition to PRL and estrogens, the TIDA/THDA neurons interact with a number of neuropeptides and neurotransmitters, as illustrated schematically in Fig. 7. Only selected factors will be discussed here to exemplify the complexity of the dopaminergic system. Opioid peptides stimulate PRL release by inhibiting the TIDA neurons. The hypothalamus contains perikarya of the three opioid classes, i.e., endorphins, dynorphins, and enkephalins, all of which participate in the regulation of PRL release under some conditions. The opioid peptides exert their effect via three major receptor types, µ, , and , which belong to the superfamily of seven transmembrane G protein-coupled receptors (for review, see Ref. 225).

View larger version (25K): [in this window] [in a new window]   Figure 7. Selected compounds that act as stimulators or inhibitors of the hypothalamic dopaminergic neurons. PRL and E2 function as the primary stimulators and inhibitors, respectively, of the dopaminergic neurons. Bombesin and neurotensin stimulate TH activity, whereas opioid peptides, CCK, serotonin, and GABA act as inhibitors. This is only a partial list, and several of these compounds have a dual action on PRL release, depending upon their sites of action. Specific actions via the TIDA or THDA neurons cannot be assigned with certainty. [Derived from M. E. Freeman et al.: Physiol Rev 80:1523:1631, 2000 (105 )].

The recognition that endogenous opioids inhibit the TIDA neurons is based on many studies with receptor agonists. Early studies employing systemic and intraventricular administration of the opioid agonist morphine reported lowered TIDA neuronal activity and reduced dopamine levels in portal blood. Conversely, central administration of either µ- or -receptor antagonists increase TIDA neuronal activity (reviewed in Refs. 105 and 113). Several lines of evidence support direct action of the opioid peptides on the TIDA neurons. One is activation of potassium conductance and hyperpolarization of dopaminergic neurons by a µ-opioid agonist (232), and another is inhibition of the firing rates of arcuate nucleus neurons in hypothalamic slices by all three classes of opioid peptides (233). A third line of evidence is the reported inhibition of dopamine release and synthesis from incubated median eminence by ß-endorphin (231) and enkephalin (234).

Interactions between opioid peptides and TH-positive neurons are especially prominent during the proestrus PRL surge (235), the nocturnal PRL rise in pregnant rats (236), and during suckling (230, 237). Stress-induced PRL release is also mediated, at least in part, by disinhibition of endogenous opioids’ control over the TIDA neurons (238). Most studies to date have used naloxone, a broad-spectrum opioid receptor antagonist. For example, infusion of naloxone to lactating rats during suckling resulted in a marked suppression of circulating PRL levels and a concomitant increase in TIDA neurons’ activity and TH expression. Such alterations occur in both the arcuate nucleus and median eminence but not in the zona incerta, establishing site specificity (237). Pups of the naloxone-treated mothers failed to gain weight, indicating lower milk availability and perhaps some inhibition of oxytocin release. As mentioned before, the TIDA neurons in males are under tonic inhibition by endogenous opioids peptides through -receptors (130). These data, supported by immunoneutralization studies (230), indicate that the endogenous opioids comprise an integral component of the system that generates PRL surges, but they do not rule out their potential interactions with nondopaminergic neurons that produce PRL releasing factors.

Cholecystokinin (CCK), produced in several molecular forms from a larger precursor protein, also increases PRL release indirectly. Originally discovered in the gut, CCK is widely distributed in the brain, where it participates in the regulation of appetite and body temperature (reviewed in Ref. 239). CCK-8, the predominant form in the brain, exerts its actions mainly through the CCK-B receptor. Both immunoreactive CCK and its receptors are highly expressed in both the arcuate nucleus and the neural lobe (240). Third-ventricular administration of CCK stimulates PRL release (241), but its mode of action is complicated by gender differences, with males responding to a central CCK antagonist with increases, but OVEX rats with decreases, in PRL release (242). CCK has a robust stimulatory effect on the firing rates of arcuate nucleus neurons (243), but because this presumably increases dopamine release, it is not consistent with an overall stimulatory effect of CCK on PRL secretion.

Other neuropeptides, e.g., bombesin, neurotensin, and NPY, inhibit PRL release by stimulating the TIDA neurons (for review, see Ref. 105). Their action, however, is often confounded by their ability to exert opposite effects on the pituitary itself. Bombesin is a 14-amino acid peptide isolated from the skin of a frog. Family members include gastrin-related peptide (GRP), neuromedins B and C, and ranatensin. Although there are many GRP-positive perikarya in the paraventricular and periventricular nuclei with projections to the SCN, there is little evidence that they innervate the arcuate nucleus or median eminence (244). Yet, these compounds have a potent stimulatory effect on unit activity of most arcuate neurons, an effect that is blocked by GRP receptor inhibitors (245). Also, intraventricular administration of bombesin-like peptides increases TIDA and PHDA activities in males, without affecting nigrostriatal or THDA neurons, and suppresses both PRL and -MSH release (115). Bombesin-like peptides may also play a role in the circadian rhythm of PRL release, acting via the SCN (246). Further evidence for a role of endogenous GRP-related peptides in the control of PRL release is provided by the rise in serum PRL after central immunoneutralization of these peptides (247).

Neurotensin is a 13-amino acid peptide generated by posttranslational processing of a large precursor protein (for review, see Ref. 248). It shows extensive colocalization with TIDA/PHDA neurons that project to the external layer of the median eminence and neurointermediate lobe (249). Like many neuropeptides, it exerts a dual action on PRL: central inhibition and peripheral stimulation (250). Neurotensin activates both the TIDA and THDA neurons and induces concomitant decreases in serum PRL and -MSH levels (251). Indirect evidence suggests that it mediates the hyperprolactinemia-induced activation of TIDA neurons in both males and females (252). The effects of NPY, the most abundant neuropeptide in the brain, on PRL release are similar to those of neurotensin except that it does not mediate the PRL feedback on the TIDA neurons (for review, see Ref. 105).

Among neurotransmitters, the stimulatory effect of serotonin on PRL release has long been recognized (reviewed in Ref. 253). Serotonergic neurons originating from the raphe nucleus terminate in many hypothalamic nuclei including the SCN, paraventricular nuclei, and arcuate nuclei with projections into the intermediate lobe (254). Early studies using drugs that enhance serotonergic function, i.e., precursors, receptor agonists, and uptake inhibitors, revealed transient rises in PRL release in rodents, but were less effective in humans. Conversely, drugs that impair serotonergic neurotransmission or lesions of the raphe nucleus and its projections prevented rises in PRL release in response to stress and suckling (for review, see Ref. 1). The stimulatory action of serotonin on PRL involves the 5-HT_2A, 5-HT_2C, and 5-HT₃ receptor subtypes (255). Although serotonin administration reduces dopamine levels in hypophysial portal blood (256) and suppresses TH activity (257), a consistent effect of serotonin agonists on TIDA neuronal activity has not been observed. Instead, the current dogma is that serotonin affects PRL secretion primarily by stimulating the release of PRF. The latter is supported by the increased PRL release from anterior pituitaries cocultured with posterior pituitaries in the presence of serotonin (258).

GABA, acting through GABA(() receptors, appears to play a role in the control of basal and diurnal changes of TIDA neuronal activity, and contributes to increased PRL secretion (259). The participation of the cholinergic system in the regulation of PRL release is controversial, and the observed effects vary with the site of administration, the dose, and the physiological conditions of the animals. There is an endogenous rhythm of cholinergic neurons, which may contribute to the circadian changes that occur in both the TIDA neuronal activity and PRL release, but whether the cholinergic output is on the opioidergic or TIDA neurons remains to be determined (113). Histamine can also be added to the list of centrally and peripherally acting neurotransmitters with an unclear mechanism of action (105, 260).

	IV. Dopamine and the Pituitary Lactotrophs

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
A. Dopamine and its receptor
Because the anterior pituitary is a non-neuronal tissue, the presence of dopamine in this lobe (121, 122), in association with PRL-containing secretory granules (261, 262, 263), raises the question as to its cellular origin. One possibility is de novo dopamine synthesis. The long-held dogma that the anterior pituitary is not innervated has been challenged by recent studies using sensitive staining and electron microscopy techniques (reviewed in Ref. 264). The presence of few TH-positive, DBH-negative fibers in the rat anterior pituitary has been reported (265), although this has not been confirmed by others (111). TH mRNA was detected in the female rat anterior pituitary by RT-PCR and in situ hybridization (266), but a subsequent study found two alternatively spliced TH transcripts that do not encode a full-size TH protein (267). The fact that TH in the anterior pituitary may be nonfunctional, together with the lack of evidence for de novo synthesis, argue against local dopamine synthesis. On the other hand, TH activity and dopamine production were detected in anterior pituitaries grafted under the kidney capsule (268), and low levels of TH protein, similar in size to that in PC12 cells, were observed by Western blotting in GH3 cells (269). Therefore, a functional TH may be produced only under abnormal conditions such as in ectopic pituitaries, adenomas, or transformed lactotrophs.

Uptake of dopamine, brought to the pituitary by portal blood, is another conceivable source of dopamine within the anterior pituitary. If this is the case, either DAT or another dopamine transporter must be involved. DAT was detected in the rat anterior pituitary by antibodies raised against a synthetic peptide (270), but this was not confirmed by others (111). Indeed, expression of DAT in the anterior pituitary represents an unusual situation because the distribution of this transporter may be restricted to the CNS, where it always colocalizes with TH (34). However, dopamine reuptake also occurs in a Na⁺-dependent manner in glial cells that do not express DAT, suggesting an alternate mechanism (271). GH3 cells were shown to take up MPP⁺, a selective dopaminergic neurotoxin that generates Parkinson’s-like symptoms (269). This uptake occurs in a concentration- dependent manner and is blocked by nomifensin, a selective dopamine reuptake inhibitor. Further exploration of dopamine uptake in the anterior pituitary, especially by lactotrophs, should provide an appealing mechanism for a local control of dopamine availability to these cells.

The predominant dopamine receptor in the pituitary, abundant in both lactotrophs and melanotrophs, is the D₂-type (73, 272). The D₂R, initially cloned from the rat brain, consists of 1245 nucleotides encoding a 415-amino acid protein (63). Subsequent studies identified a second cDNA with an 87-nucleotide insertion that encodes a 444-amino acid protein (273). Both sequences originate from a single gene spanning approximately 50 kb and containing 8 exons, with exon 1 encoding an untranslated sequence. Alternative splicing removes exon 6 and generates long and short isoforms (D₂L and D₂S, respectively), which differ in 29 amino acids in the third cytoplasmic loop that is involved in coupling to G proteins (see Fig. 8). The isoforms exhibit similar pharmacological properties and are coexpressed in the same cells, but because of select coupling to G proteins, they may serve different functions. The long isoform is predominant in the rat pituitary, striatum, and olfactory tubercle, whereas the short isoform is more abundant in the hypothalamus and the substantia nigra (274). The long isoform also predominates in normal human pituitaries (275). Activation of either isoform in rat lactotrophs mediates dopamine suppression of the PRL gene (276), with both isoforms inhibiting adenylyl cyclase but only the D₂S negatively coupled to the phospholipase signaling pathway (79, 277).

View larger version (37K): [in this window] [in a new window]   Figure 8. Diagram of the D2R. Panel A, The D2R promoter region. The primary and additional putative transcription start sites are indicated by solid and open arrows, respectively. The promoter lacks TATA and CAAT boxes and has several putative Sp1 binding sites (open ovals). Negative and positive modulatory elements are designated by hatched and dark rectangles, respectively. Panel B, Organization of the D2R gene and alternative splicing that generate the long (D2L) and short (D2S) isoforms. Exons, introns, and untranslated sequences are designated by filled boxes, connecting lines, and hatched boxes, respectively. The empty box is exon 6, which is absent in the D2S transcript. Panel C, Diagram of the D2R protein. Shown are the 7 TMDs and potential N-glycosylation, PKA phosphorylation, and palmitoylation sites. The disulfide bridge between extracellular loops and the serine residues involved in agonist binding in TMD V are also depicted. The 29-residue insert (interrupted line) in the large intracellular loop is specific to the long isoform. [Derived from R. Piceti et al.: Crit Rev Neurobiol 11:121–142, 1997 (78 )].

The effects of dopamine agonists and antagonists on pituitary D₂R expression is controversial. In one study, haloperidol increased D₂R mRNA levels in the neurointermediate lobe, whereas bromocriptine caused no change, with neither compound changing D₂R mRNA levels in the anterior lobe (272). In another study, dopamine increased the expression of D₂R in primary dispersed rat anterior pituitary cells (281). Several growth factors also alter D₂R expression by the lactotrophs. For example, exposure of GH3 cells, which lack functional D₂R, to epidermal growth factor (EGF) induces the expression of both D₂R isoforms, which were coupled to potassium channels and responded to selective dopamine agonists (282). In addition, NGF induces D₂R expression in bromocriptine-resistant human prolactinomas grown in soft agar or in nude mice (283). Ablation of NGF production by antisense oligonucleotides in bromocriptine-responsive cells resulted in loss of D₂R expression and unresponsiveness to dopamine (284). NGF treatment also induces the expression of D₂R in GH3 cells (285). Unlike the effect of EGF, NGF induced the expression of dopamine receptors that were coupled to adenylyl cyclase rather than to potassium channels.

As shown in Fig. 8, the primary transcription initiation site of the rat D₂R gene is located 320 bp upstream from the first exon, with a minor site 70 bp further upstream (286). The promoter lacks TATA and CAAT boxes and is rich in G+C content with several putative Sp1 binding sites. Consensus sequences have also been identified for AP1, AP2, GATA, and the thyroid receptor/RAR. Yet the identity of specific promoter elements and binding proteins that regulate D₂R gene transcription is unclear (287, 288). A cis-acting element, located between -75 and -30 relative to the transcription start site, positively regulates the promoter, whereas negative regulation is exerted further upstream (287). The D₂R promoter has been ligated to reporter genes and transfected into several cell types. Promoter activity is robust in cell lines that normally express D₂R with only limited activity in cells that do not (78), indicating that cell-specific transcription factors are necessary for the regulation of the D₂R gene.

B. Actions and signal transduction
Although dopamine has been recognized as the physiological inhibitor of lactotrophs for over three decades, its exact mechanism of action is less understood than that of other hypothalamic regulating factors. The reasons for this are as follows: First, it is more difficult to study inhibition than stimulation. Second, lactotrophs are highly heterogeneous with respect to basal PRL release and responsiveness to dopamine. Third, there is a paucity of lactotroph cell lines with endogenous and functional dopamine receptors. Fourth, at very low concentrations, dopamine has been reported to stimulate, rather than inhibit, PRL secretion.

Lactotrophs in vivo are continuously exposed to dopamine. When cultured without dopamine, their cellular properties may be altered, deviating from the situation in vivo. Despite this caveat, many lines of evidence indicate that dopamine exerts diverse effects on the lactotrophs. This can be best illustrated when considered on a continuous time scale. Within seconds of exposure, dopamine induces membrane hyperpolarization leading to inactivation of voltage-gated calcium channels, reduced intracellular free calcium, and inhibition of PRL release from secretory granules (see Fig. 9). Within minutes to hours, dopamine suppresses adenylyl cyclase activity and lowers inositol phosphate metabolism, resulting in the suppression of PRL gene expression and changes in cell morphology. Within days, dopamine inhibits lactotroph proliferation and decreases the size of hypertrophied lactotrophs. It remains to be determined whether all these events occur within the same cell or involve different cell subpopulations and to what extent they progress sequentially or occur in parallel.

View larger version (29K): [in this window] [in a new window]   Figure 9. Diagram of the mechanisms by which dopamine affects the pituitary lactotroph. After binding to D2R, dopamine rapidly increases intracellular potassium and reduces calcium influx. This can be done by either a direct or an indirect coupling of the receptor via G0 to potassium channels, resulting in a decrease in calcium influx and an immediate suppression of PRL release. Further decreases in intracellular calcium are achieved by inhibition of PLC and PKC, resulting in reduced calcium mobilization from the endoplasmic reticulum (ER). The main mechanism for the suppression of PRL gene expression is done by coupling of the D2R to Gi proteins, resulting in inhibition of adenylyl cyclase ((C), decreases in cAMP production, and suppression of activated PKA.

Dopamine induces a very rapid fall in cytosolic free calcium concentration, particularly in spontaneously active lactotrophs (see Fig. 9). Two mechanisms have been proposed to explain this action. One is via coupling of the D₂R to voltage-gated calcium channels (292), which are substrates for phosphorylation/dephosphorylation by PKA and PKC (293, 294). However, the dopamine-induced reduction in cAMP levels is too slow to account for the speed with which calcium oscillations are suppressed by dopamine. Instead, it may reflect more prolonged changes in channel activity that is induced by dopamine. Another proposed mechanism is that dopamine reduces calcium influx indirectly, by evoking membrane hyperpolarization via inward rectifying current that increase potassium conductance (289). This results in the closing of voltage-gated calcium channels and a rapid decline in intracellular calcium. Because PRL release from storage granules is coupled to calcium availability, these processes explain the high basal PRL release by cultured lactotrophs in the absence of dopamine and its rapid suppression upon exposure to dopamine.

Several laboratories have reported that dopamine at extremely low concentrations (<0.1 nM) stimulates PRL release (295, 296). The stimulation is rather modest and has not been observed by all investigators. Several mechanisms have been proposed to explain this phenomenon, including predominance of the short dopamine receptor isoform (297), mediation by D₁ and D₅ receptors (298), involvement of G_i3 protein (299), and dopamine-induced increases in intracellular calcium by lactotroph subpopulations (296). Opponents of this notion argue that the observed stimulation can be explained by dopamine withdrawal, resulting in increased cytosolic free calcium concentration (291) and a rebound of PRL release that exceeds baseline levels. When the rebound occurs in the presence of secretagogues such as TRH or VIP, it results in a pronounced potentiation of their PRL-releasing actions (300). Presently, the issue of the stimulatory effect of dopamine is controversial and needs further assessment.

The primary mechanism by which dopamine suppresses PRL gene expression is by reducing intracellular cAMP levels (Fig. 9). Several studies have established that dopamine inhibits adenylyl cyclase activity in the anterior pituitary in vivo and in cultured lactotrophs in vitro (for review, see Ref. 131). The D₂R is coupled to pertussis toxin-sensitive signaling pathways, implicating its association with members of the G_i/o protein family (301). Activation of the G_i- and G_o-subunits alter the activity of adenylyl cyclase types I, V, and VI (302). The Gß-subunits, released by the activation of G_i/o, can enhance the activity of type II enzyme, enabling cross-talk between several biochemical pathways. The complex interaction of these pathways after D₂R activation alters cAMP levels and, consequently, PKA activity. PKA phosphorylates cytoplasmic and nuclear proteins and also regulates ion channel function and desensitization of G protein-coupled receptors. Increases in cAMP lead to functional activation of PKA by binding to the regulatory subunits and liberating the catalytic subunits, whereas a decrease in cAMP suppresses PKA by maintaining it in an inactive conformation. It is this suppression of PKA activity, especially in the presence of secretagogues, that mediates many of the cellular responses of lactotrophs to dopamine (303), with some evidence for the involvement of PKC as well (304).

The role of IP3 as a mediator of dopamine action on the lactotrophs is unclear (Fig. 9). Although activation of D₂R in pituitary lactotrophs results in inhibition of inositol phosphate production, this is a relatively late event that may be secondary to decreased calcium influx (305). In GH4C1 cells transfected with either D₂L or D₂S receptor isoforms, only the short isoform is negatively coupled to PLC, whereas both are negatively coupled to adenylyl cyclase (79). The short isoform can also activate PLD through a pertussis toxin-independent mechanism that may involve Rho proteins (277). The cellular response to D₂R activation likely depends on the available G proteins in any given cell. The existence of two receptor isoforms that are differentially coupled to various G proteins within the same cell likely serves to amplify and diversify the response to dopamine.

Other actions of dopamine on the lactotrophs have been reported. One is an indirect suppression of the PRL gene by inhibiting the expression of Pit-1, a pituitary-specific transcription factor that is necessary for GH and PRL gene expression (for review, see Ref. 306). Incubation of dopamine agonists with GH cells transfected with D₂R reversibly inhibits Pit-1 via a dopamine-sensitive domain in the N- terminal sequence of Pit-1 (307). Dopamine also induces cortical actin assembly and stabilization in lactotrophs by increasing the expression of the actin anchoring proteins talin and -actinin and maintaining a rounded cell shape (308). Whether changes in cell shape, observed under in vitro conditions, are relevant to a physiological action of dopamine is unclear.

C. Antiproliferative activity
The best evidence supporting the antimitotic activity of dopamine on the lactotrophs comes from the induction of pituitary hyperplasia in D₂R-deficient mice and pituitary hypoplasia in DAT-deficient mice, discussed in Section V.A. In addition, bromocriptine, the dopamine receptor agonist, causes considerable shrinkage of human prolactinomas (discussed in Section VI). Here we will review evidence derived either from normal laboratory animals or from cultured cells.

Although dopamine is effective in suppressing proliferation of the melanotrophs during early postnatal development (101), a similar action of dopamine or its agonists on the developing lactotrophs has not been reported. The increase in the number of lactotrophs in females during puberty appears to be due to increased circulating levels of estrogens rather than a decreased dopaminergic tone (309). On the other hand, bromocriptine is effective in reversing the pituitary hyperplasia that is induced by exogenous estrogens in certain strains of rats, e.g., Fischer 344 (310, 311). The estrogen-induced TGF expression is rapidly attenuated by D₂R activation and is accompanied by regression of the estrogen-induced pituitary growth (312). Interaction between these opposing hormone/transmitter responses is responsible, at least in part, for the growth potential of the anterior pituitary. Whether other estrogen-responsive genes that are involved in regulating pituitary proliferation such as TGFß (313) are also affected by dopamine remains to be determined.

Cultured normal lactotrophs treated with dopamine or bromocriptine show decreased bromodeoxyuridine-labeling indices, whereas pretreatment with D₂R antagonists blocks this effect (314). The decrease in nuclear bromodeoxyuridine incorporation, reflecting a decrease in DNA replication, is consistent with an antimitotic activity of dopamine in the pituitary. Interestingly, dopamine and its agonists have neurotoxic effects on cultured neurons that can be prevented by free radical scavengers and antioxidants (315). Similar effects have been observed upon long-term incubation of GH3 cells with bromocriptine (316). However, because GH3 cells do not express functional D₂R, the cytotoxic action of bromocriptine likely occurs by a dopamine receptor-independent mechanism. Indeed, bromocriptine inhibits proliferation of several cell types, such as smooth muscle cells that do not express D₂R (317), and induces apoptosis by activating p38 MAPK in GH3 cells (318).

	V. Lessons Learned from Transgenic Mice

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
A. Dopamine D₂ receptor (D₂R) and transporter
Two types of transgenic mice with altered dopamine have been generated: those with a deletion of D₂R, which prevents dopamine action, and those with a deletion of DAT, which increases dopamine availability (see Fig. 10). Two laboratories (319, 320) independently generated D₂R mutants and described the consequences of D₂R loss on the neuroendocrine axis. The major phenotype is chronic hyperprolactinemia and lactotroph hyperplasia that develops into adenoma in aged females only. Pituitary PRL expression is robust in D₂R-null mice with a slight decrease in GH and no major change in other hormones. Null mice of either sex have a 3- to 4-fold higher basal PRL levels and, as expected, do not respond to the dopamine receptor antagonist haloperidol. Although D₂R mutant males have normal spermatogenesis, young females have irregular estrous cycles and lower serum estrogen levels, but with little impact on fertility. This differs from the impact of hyperprolactinemia on humans, which results in menstrual disturbances, anovulation, and infertility (321). D₂R-null females have higher serum PRL levels than males, underscoring the importance of estrogen in PRL biosynthesis. The lack of D₂R does not affect hypothalamic regulatory factors such as TRH and VIP, although this issue has not been examined in depth. Notably, pituitary PRL-R expression is also higher in the D₂R-deficient mice, perhaps secondary to pituitary hyperplasia.

View larger version (43K): [in this window] [in a new window]   Figure 10. Summary of the effects of various gene inactivation in transgenic mice on PRL and dopamine release and on pituitary size. The size and color of the arrows and the size of the pituitary represent increases/decreases relative to wild-type animals (normal). PRL release is increased in D2R- and PRL-R-null mice, decreased in galanin- and ER-null mice, and is undetectable in PRL-null mice. Pituitary size increases in D2R- and PRL-null mice and decreases in DAT-null mice. See Section V for more details.

The mechanisms leading to tumor formation in females and its late onset are unknown. Although PRL itself has been implicated, there is only limited evidence that PRL is mitogenic in lactotrophs (323). On the other hand, involvement of local growth factors such as galanin, normally under dopaminergic inhibition (324), should be considered. Also, a disrupted balance between angiogenic/antiangiogenic factors such as vascular endothelial growth factor (VEGF) may be responsible for the observed perturbation in the local vasculature (325).

As expected, impairment of dopamine transmission in the nigrostriatal system results in deficits in locomotion, whereas linear growth, onset of puberty, and fecundity are not altered. Expression of D₃R, D₄R, and TH in the striatum of null mice was unaffected, whereas enkephalin mRNA levels increased. The observed effects of D₂R deletion on the intermediate lobe differ between the two laboratories, given the different genetic background of the transgenic mice. Kelly et al. (320) found no difference between D₂R-deficient and wild-type mice in either cell density within the intermediate lobe or ß-endorphin content, whereas Saiardi et al. (319) reported enlargement of the intermediate lobe and increased POMC expression in null mice.

Deletion of DAT results in an almost opposite phenotype to that of D₂R deficiency (see Fig. 10). DAT-null mice have increased dopaminergic tone, anterior pituitary hypoplasia, dwarfism, and inability to lactate (112). Pituitary hypoplasia is due to decreased number of lactotrophs and somatotrophs without a change in thyrotrophs or gonadotrophs. With more dopamine presumably reaching the pituitary, one would expect a reduction in pituitary PRL content, due to down-regulation of the PRL gene, and a suppression of serum PRL levels. However, the DAT-deficient mice present two unexpected outcomes, an unchanged basal serum PRL level despite a 70–80% reduction in pituitary PRL content, and unresponsiveness to the dopamine receptor antagonist sulpiride.

Perhaps the major effect of a higher dopamine input at an early age due to DAT deficiency is on lactotroph development, selection or survival. Rapid PRL turnover in the remaining lactotrophs or increased sensitivity to PRL secretagogues may account for the maintenance of near normal basal serum PRL levels. Compensatory mechanisms acting to diminish the effects of enhanced dopamine input could be responsible for lactotroph unresponsiveness to the blockade of D₂R. These include down-regulation of the D₂R or suppression of TH, thereby reducing dopamine input to the lactotrophs. The inability to lactate despite normal circulating PRL levels could be due to several factors, including pituitary insensitivity to PRL secretagogues or insufficient pituitary PRL reserves needed for development/maturation of the mammary gland and milk production.

The mechanism leading to dwarfism in DAT-deficient mice is also of interest. There is a marked decrease in the number of somatotrophs and a reduced pituitary GH content, but circulating GH levels are normal. The expression of Pit-1 at ED 16.5 is similar in DAT-null and controls, but is 50% lower in adult DAT-deficient mice. The lower Pit-1 expression in adults may be the result of reduced number of pituitary cells expressing Pit-1 or due to suppression of Pit-1 expression by the enhanced dopamine input. Indeed, there is evidence from cultured cells that dopamine suppresses Pit-1 expression (326). Increased dopamine availability also results in lower GHRH expression with no change in somatostatin. As most GHRH neurons are located in the arcuate nucleus adjacent to the TIDA neurons (327), suppression of GHRH by elevated dopamine may decrease the supply of GHRH to the anterior pituitary, resulting in failure of somatotroph proliferation or maintenance and the resultant dwarfism.

B. PRL and PRL receptor (PRL-R)
Two laboratories have generated transgenic mice with PRL deficiencies: one resulting from deletion of the PRL-R (328) and another resulting from targeted mutation of the PRL gene (329). Unlike humans who have a single transcript, mice have 1 long and 3 short PRL-R isoforms (330). Deletion of exon 5 in the mouse PRL-R gene results in undetectable levels of the receptor protein and lack of specific binding of PRL to liver microsomes, confirming the absence of functional PRL-Rs. In contrast, the PRL gene was mutated by inserting a neomycin resistance gene downstream of the bases encoding Ser 117 in exon 4, resulting in the production of an 11-kDa immunoreactive PRL fragment by the pituitary. However, this truncated PRL is biologically inactive, as judged by the Nb2 proliferation bioassay, but can be used as a cellular marker to identify the lactotrophs. Although the truncated product is close in size to 16-kDa PRL reported to possess antiangiogenic properties (331), there is no evidence that they share similar properties.

Among the observed characteristics of these transgenic mice, we will focus on those most relevant to the neuroendocrine axis (see Fig. 10). Shared features by both mutants include irregular estrous cyclicity, absence of pseudopregnancy, abnormal mammary development, and sterility. Despite repeated mating and the presence of oviductal ova, there is an almost complete arrest of preimplantation embryo development in PRL-R-null mice. Because their fertilized eggs develop into normal offspring in foster intact dams, a deficiency in oviductal environment is indicated rather than an abnormal oocyte development. The failure of the uterus to support blastocyst implantation, secondary to lack of PRL-supported progesterone production by the corpus luteum, renders these animals unable to maintain pregnancy. Progesterone replacement in PRL-R-null mice rescues embryo implantation and facilitates maintenance of pregnancy to term (332). Notably, the luteotropic function of PRL is unique to rodents and does not apply to most other species. Males with a disrupted PRL gene are fully fertile, whereas some males with a disrupted receptor show delayed fertility that is corrected over time. As expected, mammary gland development is abnormal in both types of mice, with unchanged ductal branching but absence of terminal or lateral lobulation.

The ligand- and receptor-deficient mice differ in several respects. One is mammary gland development in heterozygotes. Whereas mice heterozygous for PRL produce a normal litter size and have no problems nursing their young, the PRL-R-heterozygotes have impaired lactation during their first pregnancy, which is restored with successive pregnancies. This suggests that two functional alleles of the PRL-R are required for efficient mammary gland development, with hormones other than PRL (gonadal steroids, GH, and placental lactogens) providing sufficient delayed stimulation for the development of lactation-competent mammary glands. In contrast, sufficient levels of PRL can be synthesized from a single allele in PRL heterozygotes. Maternal behavior, as judged by the latency of pup retrieval and crouching, is severely impaired in the PRL-R heterozygotes (333), but appears to be normal in either homozygote or heterozygote PRL-deficient mice (329). This difference may involve PRL-like hormones (e.g., placental lactogens) that act via the brain PRL-R to modify maternal behavior.

The hypothalamo-pituitary axis has not been extensively studied in either type of PRL-deficient mice. Plasma PRL in the receptor-null mice is increased 30-fold in males and 100-fold in females, with a somewhat larger pituitary size and an increased blood supply. Treatment of PRL-R-deficient mice with bromocriptine normalizes PRL levels, indicating retention of D₂R responsiveness by the lactotrophs. Although hypothalamic dopamine has not been examined in these animals, one would predict that the absence of PRL-R on the TIDA/THDA neurons results in reduced synthesis/release of dopamine as a compensatory response for a perceived lack of PRL. In the PRL-deficient females, the intensity of dopamine fluorescence and TH immunoreactivity are reduced in the A12 neurons, but the number of TIDA neurons is unchanged (334). In the PRL-deficient males, dopamine content in the median eminence, but not in the medial basal hypothalamus, is reduced by 50%, with no change in norepinephrine (335).

Perhaps the most striking, and unexpected, outcome of PRL deficiency is pituitary hyperplasia that is seen already in young (6–8 wk) males and females, developing into very large and hemorrhagic adenomas in aged females. This is similar to the late onset adenoma that develops in D₂R-knockout female mice, which have impaired dopaminergic inhibition but elevated PRL levels (Fig. 10). The common feature to the two types of transgenic mice is loss of negative growth control by dopamine, which might involve mediation by local factors such as galanin.

Transgenic mice overexpressing PRL or other lactogenic hormones have also been generated (for review, see Ref. 336). Although PRL hypersecretion for short periods can be achieved by antidopaminergic drugs or pituitary transplantation, transgenic animals overexpressing PRL offer the opportunity for exploring the physiological consequences of a lifelong exposure to excess PRL. Overexpression of the rat PRL gene in mice resulted in circulating levels of PRL as high as 250 ng/ml, a dramatic enlargement of the prostate gland (337), an increase in the expression of PRL-R in both adipose tissue and liver (338), and the development of mammary carcinomas at 11–15 months of age (338A ). Transgenic mice overexpressing human GH (hGH) are also of interest because hGH has both somatogenic and lactogenic activities in rodents, resulting in physiological hyperprolactinemia and hypersomatotropism (336). Transgenic females expressing moderate amounts of hGH have low circulating PRL levels, luteal deficiency, and sterility. This appears to be due to stimulation of hypothalamic dopamine by binding of hGH to the PRL-R, resulting in a 35–50% increase in the number of TH-immunoreactive neurons in the A12, but not A13, neuronal groups (339). This effect was not seen in animals overexpressing bovine GH, which is not lactogenic.

C. ERs, galanin, and nerve growth factor (NGF)
The recent generation of ER- and ERß-deficient mice, named ERKO and ßERKO respectively, helped in defining the diverse actions of estrogens. Most attention has been focused on the reproductive tract with only limited examination of the neuroendocrine axis that regulates PRL. Unlike the rat and human, the ERß transcript is very low or undetectable in the normal mouse pituitary, whereas both receptors are expressed in the hypothalamus, with a predominance of ER (for review, see Ref. 340). The ERKO males and females exhibit a 10- and 20-fold reduction in pituitary PRL mRNA levels compared with wild-type animals (see Fig. 10). The change in circulating PRL levels in females is less dramatic, showing only a 5-fold decrease, suggestive of compensatory mechanisms. The reduction in pituitary PRL expression in ERKO females is more severe than that seen in OVEX wild type mice, raising the possibility of a decreased number of lactotrophs (341). Neither TIDA/THDA neurons nor pituitary D₂R expression have been evaluated in these animals.

ßERKO females have reduced fertility due to follicular arrest but exhibit normal pregnancy and lactation (342, 343). This, and the fact that ERß is not expressed in the mouse pituitary suggest that, unlike the rat, ERß does not play an important role in pituitary physiology in the mouse. However, because ERß is expressed in the arcuate nucleus (194), some subtle changes in dopaminergic neurons may be evident in ßERKO mice.

Galanin is a 29-amino acid peptide that is highly expressed in both the hypothalamus and pituitary gland. It is synthesized primarily by the lactotrophs where it is colocalized with PRL-containing secretory granules (344). Like PRL, galanin is very sensitive to estrogens. In estrogen-treated F344 rats, galanin expression increases 1000-fold above that in OVEX animals (344). In addition, TRH and dopamine stimulate and inhibit, respectively, galanin release from cultured anterior pituitary cells (324). Galanin-containing neurons are also found in the arcuate nucleus, and like the TIDA/THDA neurons, they project to both the median eminence and posterior pituitary (345). Galanin is involved in a number of functions, including feeding behavior, memory and cognition, and regulation of pituitary function. Galanin exerts its actions by binding to one of several receptor subtypes, all of which are members of the large family of G protein-coupled receptors, but with little homology to other neuropeptide receptors.

Recently, two types of transgenic mice were generated, one with galanin deficiency and another with pituitary- selective galanin overexpression. These mice show opposite effects on PRL production and lactotroph proliferation. The galanin-deficient mice were produced by deleting the entire coding region for galanin, resulting in undetectable levels of galanin (346). These mice are viable, grow normally, undergo puberty at the appropriate time, and are fully fertile. Pituitary PRL mRNA levels and contents in the galanin-deficient mice are reduced 30–40%, but basal serum PRL levels are unchanged (see Fig. 10). Mutant females, however, are unable to lactate, at least after the first two pregnancies, a likely result of markedly reduced plasma PRL levels. Their response to estrogen is also impaired. Similar to the situation in PRL-R-heterozygotes, subsequent pregnancies restore some of the lactation capability, suggesting delayed maturation of the mammary glands in the galanin-deficient mice. Pituitary expression of other hormones, including GH and LH, are unchanged in the mutants, as are hypothalamic VIP and TRH levels. There is no information on the status of hypothalamic dopamine in these animals.

Transgenic mice with pituitary overexpression of galanin carry a transgene composed of the mouse galanin gene ligated downstream of a 2.5-kb fragment of the rat PRL promoter (347). Both male and female transgenics have 100- to 1000-fold increases in galanin mRNA and peptide levels in the anterior pituitary, with no effects on the posterior pituitary or hypothalamus. The effect of galanin overexpression on hypothalamic hormones has not been examined. In 2- to 4-month-old transgenic females, pituitary PRL content is increased but plasma PRL levels do not rise until 6 months of age; other pituitary hormones, including GH, TSH, and LH, show little or no change. By 12 months, female pituitaries are hyperplastic with a higher number of lactotrophs and increased PRL gene expression, whereas males show no change. Estrogen is likely the driving force for these alterations, as judged by its ability to increase plasma PRL levels in the transgenic males and the suppression of PRL release after OVEX of transgenic females. About 20% of the hyperplastic pituitaries in 12-month-old females develop into adenomas. Again, the mechanism for increased lactotroph proliferation in the presence of estrogen is unclear and may involve a reduction in dopamine input, a direct action of galanin, or effects of any other local mitogenic factor that is regulated by estrogen, dopamine, or both.

NGF is a neurotropic factor known for its ability to induce and sustain a neuronal phenotype, particularly in peripheral sympathetic and sensory neurons. NGF acts via two transmembrane receptors, the high affinity trkA with an intrinsic tyrosine kinase activity, and the low affinity p75^NGFR, which functions as an enhancer of Trk receptor activity and also binds other neurotropins (for review, see Refs. 348 and 349). NGF and its receptors have been detected within the pituitary, and NGF is now considered as one of many autocrine/paracrine factors that affect pituitary function in various ways (for review, see Refs. 350 and 351). NGF is expressed in both the anterior and intermediate lobes (352), although its precise expression by the different pituitary cell types is controversial. There is immunohistochemical evidence for colocalization of NGF in storage vesicles within the lactotrophs, supported by the fact that VIP and the dopamine agonist quinpirole stimulated and inhibited, respectively, the secretion of both PRL and NGF (353).

Transgenic mice overexpressing NGF in the anterior pituitary were generated by fusing the mouse NGF cDNA to the PRL promoter (354). These transgenics were created to examine whether ectopic NGF would attract innervation to the anterior pituitary. Although the overexpressed NGF failed to induce pituitary innervation, it caused dramatic lactotroph hyperplasia, with the pituitary enlarged more than 50-fold above its normal size. The effect of NGF overexpression on dopamine neurons and D₂R expression have not been determined in these studies. Later studies provided evidence that NGF plays a role in mitosis and differentiation of the lactotrophs, especially during early neonatal life (355, 356).

	VI. Clinical Aspects

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
A. PRL physiology in humans
The physiology of PRL in humans differs considerably from that in rodents and will be briefly summarized (see also Fig. 11). During embryogenesis, lactotrophs are derived from progenitor bihormonal somatomammotrophs and are the last pituitary cell type to differentiate. Although GH- producing cells are detectable in the fetal pituitary at 10 wk gestation, an appreciable number of PRL-positive cells is seen only at 15–17 wk (for review, see Refs. 357, 358, 359, 360). Pituitary PRL content increases steadily from mid to late gestation without an apparent difference between the sexes. Lactotrophs comprise 10% of the total pituitary cell population at 15 wk, increase to 15% and 30% at 20 and 36 wk, respectively, and reach up to 40% of total pituitary cell population at delivery (357). Despite the scarcity of PRL-positive cells in the early embryo, PRL is detectable as early as 5–6 wk gestation in fetal pituitary cultures and in umbilical cord plasma. Fetal plasma PRL levels are low between 10 and 20 wk gestation and rise progressively to peak levels before birth. An additional rise occurs immediately after birth, persisting for several days and declining during the first postnatal month. During childhood, there are no sex differences in serum PRL concentrations, but concentrations are twice as high in women relative to men after puberty.

View larger version (25K): [in this window] [in a new window]   Figure 11. Schematic presentation of PRL levels in humans under various physiological conditions. The levels shown are approximations and do not reflect acute changes such as diurnal variations or suckling-induced rises. Note the different scale for amniotic fluid PRL.

PRL in the maternal circulation increases progressively toward term, when its concentration is 7- to 10-fold higher than that in nonpregnant women (Fig. 11). These high PRL levels are essential for the preparation of the breast for the initiation of lactation, which is prevented during pregnancy by the high levels of progesterone. Pregnancy is also associated with lactotroph hypertrophy and hyperplasia, accounting for a considerable enlargement of the pituitary. There is also a marked increase in pituitary vascularization, which may be the consequence of increased VEGF production by lactotrophs (325, 365). The role of estrogens in these processes is presumed but unproven. Active labor initiates a bimodal change in maternal serum PRL levels, an initial drop followed by a rise immediately after delivery that lasts for several hours (366). Neural signals from the cervix trigger the PRL surge during labor, because it is not seen during cesarean delivery (367), but its functional significance is unknown.

During pregnancy, large amounts of PRL are independently produced by the decidua (for review, see Ref. 368). Although decidual PRL is identical with pituitary PRL (except for a higher ratio of glycosylated PRL), its expression is driven by an alternative promoter (369) and its release is regulated by an entirely different control mechanism. Unlike the pituitary lactotrophs, which possess dense secretory granules, decidual cells have little storage capacity. Indeed, decidual PRL is rapidly released after synthesis and is not affected by increased extracellular calcium. This is unusual for cells that secrete protein hormones and is more typical of steroid-producing cells. Neither dopamine nor estrogen affect PRL release from decidual explants (370). Progesterone is mandatory for decidualization but does not act as a PRL secretagogue per se (371). IGF-I, insulin, and relaxin stimulate decidual PRL release, whereas lipocortin-1 and endothelins and several interleukins are inhibitory (for review, see Ref. 368). Decidual PRL is secreted into the amniotic fluid (see Fig. 11), where its concentrations peak between 18–23 wk gestation, attaining 50- to 100-fold higher levels than those in either the fetal or maternal circulation (372, 373). Despite the intimate contacts between amniotic fluid PRL and the developing fetus, its role in fetal physiology is unclear.

Basal PRL levels remain elevated during the first 2–3 wk postpartum in women who do not breast feed and then decline (Fig. 11). Suckling is the most potent and best characterized physiological stimulus for PRL release. The magnitude of the suckling-induced PRL rise is robust during early lactation but wanes thereafter (374). Tactile stimuli of the breast can increase serum PRL in nonlactating women but not in men (375). Lactational amenorrhea, used by some postpartum women as a method of contraception, appears to be more associated with the frequency and duration of the suckling episodes rather than due to a persistent hyperprolactinemia (376).

Estrogens are responsible for the higher basal serum PRL levels, the enhanced responsiveness to PRL secretagogues, and the higher incidence of prolactinomas in women than men. In contrast to rats, estrogens have little effect on acute PRL release in humans. Circulating PRL levels do not increase during the preovulatory LH surge and are basically unchanged throughout the menstrual cycle (377). Also, oral contraceptives do not appreciably increase serum PRL levels and do not contribute to prolactinoma development or growth. There are only a few studies on the in vitro effects of estrogens on human lactotrophs. Cultured lactotrophs from midterm fetal pituitaries do not respond to E2 (358), although they already express both ER and ERß at this time (378). However, E2 increases PRL release from acutely dispersed adult human pituitary cells, but does not reverse the dopamine-mediated inhibition (378A ). This indicates that estrogen is a more effective stimulator of lactotrophs when the dopaminergic inhibition is absent or reduced. Studies with monkeys also suggest that there is no simple causal relationship between estrogen and PRL release (360).

Stress conditions, including anesthesia, surgery, electric shock, strenuous exercise, and insulin-induced hypoglycemia, also stimulate PRL release in both men and women (for reviews, see Refs. 360 and 379). There are also small increases in PRL in response to high protein meals, attributed to the specific action of phenylalanine and tyrosine (380). Administration of naloxone, phentolamine, or propranolol does not alter the PRL response to test meals, indicating that neither opioid, -adrenergic, nor ß-adrenergic stimulation mediate the meal-induced PRL release. The diurnal changes in circulating PRL levels in humans are also of interest. When sampled at high frequency, serum PRL levels exhibit an episodic pattern of release with as many as 5–15 secretory episodes per day. The amplitude of these pulses increases within 60–90 min after the onset of sleep, occurring primarily during the non-rapid eye movement periods (381). Unlike the situation in the rat, the diurnal variation in PRL secretion is evident in both men and women and is sleep induced rather than driven by an inherent diurnal rhythm.

B. Drug-induced PRL release
Drugs that interfere with dopaminergic neurotransmission, either by increasing its availability or by reducing its effectiveness, often, but not always, affect PRL homeostasis. The following diseases, which require long-term treatment with dopamine-altering drugs, will be briefly discussed: Parkinson’s, schizophrenia, depression, and hypertension (see summary in Table 1). In addition, opioidergic drugs that interact with the hypothalamic dopaminergic system are used for alleviating chronic pain and for pain management in cancer patients. The effects of these medications on PRL release vary with the type of drug, doses, and duration of treatment (for review, see Ref. 382).

Perhaps due to the lack of dopamine autoreceptors, a sluggish reuptake mechanism, or protective effects of local neurotropic factors, the function of the TIDA neurons is conserved in Parkinson’s disease and untreated patients have normal basal, as well as episodic, PRL release (385). L-Dopa, which can cross the blood brain barrier, remains the mainstay of therapy for replenishing dopamine, but unfavorable side effects such as fluctuations in motor performance and psychosis have led to the development of new dopaminergic and nondopaminergic drugs. Among the former are D₂R agonists such as bromocriptine, lisuride, pergolide, and cabergoline (see Table 1). Several studies have assessed the effects of long term L-DOPA therapy alone or in combination with D₂R agonists on the neuroendocrine system (92, 386). They found suppressed serum PRL and TSH levels and elevated GH levels but unchanged PRL responsiveness to TRH. Because there are no documented effects of prolonged hypoprolactinemia in humans, it can be concluded that treatment of Parkinson’s patients with dopaminergic agonists has minimal prolonged consequences on the physiology of PRL.

Schizophrenia is a life-long mental illness with an early onset in teens and young adults that affects as much as 1% of the world’s population. Its etiology is complex, involving genetic predisposition, perinatal developmental factors, viral infection, and nutritional deficiency (for review, see Refs. 387 and 388). Clinical manifestations of schizophrenia are rather broad, including hallucinations and delusions, disorders of thought as well as of cognitive and social behavior, and some physical abnormalities. Males are more frequently and more severely affected than females. Unlike Alzheimer’s or Parkinson’s disease, both of which are characterized by well-defined neurotransmitter deficiency or recognizable neuropathological markers, the anatomical/neurochemical abnormalities in schizophrenia are obscure and widespread. Reported structural or functional abnormalities in schizophrenic patients include enlargement of the ventricles, decreased cerebral blood flow, and morphological alterations in the hippocampus and prefrontal cortex. Nonetheless, the general consensus is that schizophrenia is a functional rather than a neurodegenerative disorder.

Hyperdopaminergia is a prominent theory proposed over 40 yr ago in an attempt to explain the neurochemical basis of schizophrenia (for review, see Refs. 76 , 389 , and 390). This theory was based on the effectiveness of antipsychotic drugs that block dopamine receptors to alleviate many symptoms of the disease, whereas drugs that increase dopamine availability, e.g., L-DOPA, and dopamine reuptake inhibitors such as cocaine and amphetamine, produce schizophrenic-like psychoses. There is also some evidence from postmortem specimens for higher concentrations of dopamine and homovanillic acid and increased density of D₂R in certain brain regions of schizophrenics, findings that are supported by CSF sampling (391) and in vivo neuroimaging (392) in subsets of patients. More recent theories, while not disputing the central role played by dopamine, extend the putative dysfunctions in schizophrenia to alterations in neural circuitry involving serotonin, glutamate, and cholinergic neurotransmitters among others (76, 390).

The first-generation neuroleptics shared an ability to suppress dopamine neurotransmission and included drugs such as chloropromazine, haloperidol, and trifluoperazine. Although classical neuroleptics were generally effective in treating delusions and hallucinations, they fell short of improving many cognitive deficits. Moreover, they invariably caused severe sedative, hypotensive, and extrapyramidal (Parkinson’s-like) side effects (393). Most classical neuroleptics also induce significant increases in serum PRL levels (see Table 1), although few studies observed no changes (reviewed in Ref. 394). Some of the discrepancies between studies can be explained by differences in the responsiveness between men and women, drug specificity, the ratio of bioactive to immunoreactive PRL, and the presence of serum PRL binding proteins (395, 396, 397). Amenorrhea in some female patients and sexual dysfunction in some men are also indicative of increased circulating PRL levels in response to neuroleptics (394).

The adverse effects of neuroleptics, together with the recognition that hyperactivity of dopaminergic neurons does not fully explain schizophrenia, have led to the development of a second generation of antipsychotic drugs, the atypical neuroleptics. These drugs, which include clozapine, risperidone, and olanzepine among others, do not produce significant extrapyramidal side effects, although they still cause some undesirable sedative and hypotensive effects (393). The improved efficacy of these drugs on cognitive functions is attributed, in part, to a high serotonin-to-dopamine receptor blockade ratio. Most of these drugs produce little or no clinically significant PRL elevation except for risperidone, which is comparable to classical neuroleptics in its proclivity to raise serum PRL levels (394).

Serotonin receptor agonists and reuptake inhibitors are widely used in the treatment of depression. Studies with experimental animals established that drugs that increase serotonergic and opiodergic efficacy stimulate PRL release by suppressing the hypothalamic dopaminergic system (reviewed in Refs. 105 , 113 , and 253). However, with the exception of the serotonin reuptake inhibitors D-fenfluramine and desimipramine, which increase PRL release (see Table 1), most other serotonergic drugs have little effect on circulating PRL levels in humans (398). On the other hand, monoamine oxidase inhibitors such as moclobemide, also used as antidepressants, induce both acute and prolonged rises in plasma PRL levels (399).

Another class of drugs with a potential to affect PRL release are the opioid modulating drugs used in pain management (Table 1). Early studies reported that morphine, methadone, and met-enkephalin analogs increase circulating PRL levels in normal male volunteers (400). More recent studies found gender differences in the response to some of these drugs (401), and a preferential activation of the - opioid receptors (402). A few other drugs in clinical practice also affect PRL release. Among these are the D₂R antagonists metoclopramide and domperidone, used in the treatment of gastric motility disorders (403), verapamil, a calcium channel blocker used in the treatment of cardiovascular disease (404), and -methyldopa and reserpine, used in the treatment of hypertension (405).

C. Hyperprolactinemia and pituitary prolactinomas
Pathological hyperprolactinemia is defined as a consistent elevation of serum PRL levels above 20 ng/ml in nonpregnant, nonlactating individuals (reviewed in Refs. 321 , 406 , and 407). After excluding drug effects, hypothyroidism, chronic renal failure, and cirrhosis, elevated serum PRL levels are highly predictive of hypothalamic disease or pituitary tumors. The term "hypothalamic disease" covers several disorders that include tumors (e.g., craniopharyngiomas, gliomas, or meningiomas), vascular disturbances, and trauma to the pituitary stalk, all of which interfere with dopamine delivery to the pituitary. With respect to pituitary tumors, a distinction should be made between prolactinomas that release excess amounts of PRL and large adenomas that may compress the pituitary stalk or invade into the hypothalamus, resulting in increased PRL release due to dopamine deprivation. Radiologically diagnosed large adenomas with serum PRL levels below 100–150 ng/ml are suggestive of non-PRL secreting tumors rather than prolactinomas. On the other hand, the levels of PRL that are secreted by prolactinomas are usually proportional to tumor size and can reach circulating levels as high as 5,000–10,000 ng/ml.

Pituitary tumors are nonmetastasizing adenomas with diverse hormonal, cytological, and proliferative characteristics. In addition to primary classification according to the secreted hormone, they are subclassified by size, anatomical location, and invasive properties. The incidence of adenomas in the general population, based on radiological and postmortem analysis, has been estimated as high as 15–20%, but most are asymptomatic (for review, see Refs. 407 and 408). Clinically diagnosed pituitary adenomas represent 10% of all intracranial tumors. Prolactinomas or mixed PRL-/GH-secreting tumors are the most common pituitary adenomas, with an overall higher incidence in women then men. Prolactinomas are generally divided into three categories: microprolactinomas (<10 mm in diameter), macroprolactinomas (>10 mm in diameter), and macroprolactinomas with extrasellar invasion. Although invasive prolactinomas can compress the optic chiasm, cause hypothalamic damage, and erode the third ventricle, they are seldom metastatic, and true carcinomas of pituitary origin are very rare.

Two hypotheses were put forward to explain the pathogenesis of prolactinomas: dopamine dysregulation and local somatic mutation (for review, see Refs. 408 and 409). Prolactinoma formation due to loss of dopamine inhibition is supported by several observations. Among these are development of large prolactinomas in transgenic mice with D₂R deletion (322), and estrogen-induced prolactinomas in Fischer 344 rats that involve pituitary neovascularization and an escape from dopaminergic inhibition (410). In humans, the resistance of some prolactinomas to dopamine has been taken as evidence for altered dopaminergic receptor or postreceptor regulatory control. On the other hand, prolonged dopamine deficits in humans caused by neuroleptics or pituitary stalk dysfunction do not induce prolactinomas. Also, most tumors are confined to a portion of the pituitary rather than presenting as a widespread hyperplasia. Further, there is a relatively low frequency of recurrence after successful tumor resection. Collectively, these observations argue against loss of dopamine inhibition as the primary cause of prolactinoma formation in humans despite evidence to the contrary obtained in animal studies.

The local somatic mutation hypothesis is based on X-chromosomal inactivation analysis showing that almost all human pituitary adenomas are monoclonal (411, 412). This is consistent with tumor origin from a single cell that has undergone genomic mutation(s) followed by clonal expansion. The clonality of adenomas has prompted a search for genetic abnormalities such as loss of tumor suppressor genes or activation of protooncogenes that may explain the abnormal cell proliferation. However, alterations in p53 and retinoblastoma genes are very uncommon in prolactinomas, as are rearrangement, amplification, or mutations of oncogenes such as myc, ras, c-erbB2 (neu), and G proteins. Interestingly, somatic mutations in G proteins have been identified in 30–40% of GH-secreting adenomas (409). Despite evidence for loss of heterozygocity on the long arm of chromosome 11, where the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene is located, inactivation of this gene in sporadic pituitary adenomas is rare (413). Recently, a pituitary tumor transforming gene, originally cloned from GH3 cells (414), was found to be over-expressed in most PRL- and GH-secreting human pituitary adenomas (415). Further examination showed that the pituitary tumor transforming gene (PTTG) induces expression of fibroblast growth factor-2, may promote angiogenesis, and is expressed in several types of human cancer (416), but its potential role in the pathogenesis of prolactinomas remains to be determined.

In view of these conflicting findings, an integrated approach that reconciles the two theories has emerged (408). This theory stipulates genomic alteration (the identity of which remains unknown) that transforms a single lactotroph as the initial step. The transformed cell escapes normal cell cycle regulation and starts proliferating in response to local growth factors that are abundant in the pituitary such as fibroblast growth factor, EGF, TGF, or TGFß. Given that the transformed cells proliferate faster than normal cells, they are at an increased risk of additional genetic alterations, further promoting tumor progression. Among these could be loss of responsiveness to dopamine due to mutations in the D₂R or its signaling pathways. Although some reduction in D₂R expression and receptor density has been reported in prolactinomas (79), this applies only to the 10–15% of tumors that are resistant to bromocriptine therapy and does not offer a universal mechanism that explains the pathogenesis of prolactinomas. It is also important to emphasize that microprolactinomas in most patients grow very slowly and do not normally progress to become macroprolactinomas (407), suggesting a different etiology of the two types of tumors.

Gonadal dysfunction leading to infertility is a major clinical manifestation of hyperprolactinemia in women. Large tumors may also cause neurological symptoms such as headache and visual field disturbances that are related to tumor mass (for review, see Refs. 321 , 406 , and 417). Galactorrhea, or inappropriate milk production, is seen in a large percentage of hyperprolactinemic women, although it can also occur in normoprolactinemic women. Common symptoms of hyperprolactinemia in women of reproductive age are amenorrhea, oligomenorrhea, and infertility. High PRL levels are believed to inhibit release of gonadotropins (418), presumably by affecting GnRH pulsatility. This is supported by the detection of PRL-R in the GnRH-expressing GT1 neuronal cell line and the suppression of GnRH release from these cells by PRL (419). Direct effects of hyperprolactinemia on both the pituitary and ovary have also been postulated (321, 420). Other, less frequent, symptoms are decreased libido and increased anxiety and depression. Hypoestrogenism associated with hyperprolactinemia can result in osteopenia in premenopausal women, but hyperprolactinemia may decrease bone density independently of the hypoestrogenic state (421). Bone density may be re-established in many women upon restoration of normal menstrual function with dopamine agonists.

Macroprolactinomas are more common in men than women. It is unclear, however, whether this is due to a true gender-specific difference in tumor pathogenesis or because of delayed diagnosis in men compared with women that are presented with menstrual irregularities (422). About 80–90% of men with prolactinomas experience some sexual dysfunction, such as diminished libido and/or impotence. The relatively low serum T levels and some decrease in sperm counts and motility are generally attributed to decreased pulsatile secretion of LH and FSH, although infertility is not a major clinical presentation. Different studies report that between 5–20% of males with impotence are hyperprolactinemic, but there is no ready explanation for the mechanism by which hyperprolactinemia causes erectile dysfunction (423). A small percentage of men with prolactinomas (10–20%) also have galactorrhea.

D. Treatment of hyperprolactinemia
Once hyperprolactinemia is confirmed by hormone assays, radiological evaluation by means of magnetic resonance imaging or high resolution computed tomography is essential for verifying the presence or absence of pituitary adenoma. Microprolactinomas, which normally grow very slowly, can be left untreated if the symptoms are not bothersome and the patient does not wish to correct menstrual disturbances, infertility, sexual dysfunction, or hypoestrogenism. On the other hand, macroprolactinomas often cause neurological problems in addition to functional hyperprolactinemia and should normally be treated. One rare complication of macroadenomas is pituitary apoplexy, a severe form of acute intratumoral hemorrhage that can be life threatening and may lead to permanent hypopituitarism (reviewed in Ref. 424). Apoplexy is presented as a sudden onset of headache, visual impairment, nausea, and disturbance of consciousness, often warranting immediate neurosurgery for tumor decompression. Although apoplexy can occur spontaneously, predisposing factors include obstetrics hemorrhage (Sheehan syndrome), anticoagulant therapy, cardiac surgery, brain angiography, head trauma, and hypothalamo-pituitary function tests with clomiphene, TRH, and GnRH (425, 426).

The treatment of prolactinomas includes surgical resection, radiation, and therapy with dopamine agonists. Several large studies reveal that transsphenoidal surgery for tumor removal can result in normal plasma PRL levels in 60–70% of patients with microprolactinomas and in 25–30% of those with macroprolactinomas (for review, see Refs. 406 and 407). The mortality rate is less than 1%, and major complications of surgery include CSF rhinorrhea and transient diabetes insipidus. The larger the tumor, the lower the curative success rate and the higher the recurrence rate. Pituitary irradiation in the treatment of prolactinomas is less common, and data of its success are more limited. Since the early 1970s, surgery with or without radiotherapy has been progressively replaced by dopamine agonist therapy and is now generally reserved for patients who do not respond to dopamine, are intolerant of dopamine agonists, or do not wish to undergo years of medical therapy.

Bromocriptine was the first dopamine agonist to be widely used in the treatment of hyperprolactinemia (see Table 1). This ergot alkaloid has been introduced into medical practice after extensive characterization of its binding to dopamine receptors, inhibition of PRL secretion in vitro and in vivo, and suppression of tumor size in animal studies (for review, see Ref. 427). Treatment of hyperprolactinemic women with bromocriptine results in normoprolactinemia and return to ovulatory menses in 70–90% of patients (428). A similar success rate in correcting serum PRL levels and sexual dysfunction has been reported for male patients treated with bromocriptine (422). The effectiveness of bromocriptine in reducing tumor size varies among patients and length of treatment and does not always correlate well with circulating PRL levels. The 5–15% of tumors that do not respond to bromocriptine appear to be due to low expression of D₂R and possibly result from a decrease in the relative proportion of the short receptor isoform (429).

Nausea, vomiting, and orthostatic hypotension are among the most common side effects of bromocriptine therapy. These are usually transient and can be alleviated by adjusting the doses; further improvement has been achieved by intravaginal administration of bromocriptine. As expected, bromocriptine administration may exacerbate preexisting schizophrenia. Potential adverse effects of bromocriptine therapy in pregnant women with prolactinomas have been of special concern. However, data collected to date show no increase in miscarriages, ectopic pregnancies, congenital malformation, or long-term effects on the offspring (407).

Several other dopamine agonists, e.g., pergolide and lisuride as well as the more selective D₂R receptor agonists quinegolide and cabergoline (Table 1), have been used in the pharmacotherapy of prolactinomas (407, 417). Pergolide has been extensively used for treating Parkinson’s disease but has also been proven as effective as bromocriptine in the treatment of hyperprolactinemia, with some variation among patients. In several recent studies, cabergoline, an ergoline derivative, has been rated as good or better than bromocriptine for normalizing serum PRL levels as well as for inducing tumor shrinkage (430). The main advantage of cabergoline is its long-lasting properties, having a duration of action up to 2–3 wk after a single oral dose. Because cabergoline has not been in practice for an extended period of time, it is not recommended for treatment of fertility until its safety during pregnancy and the question of potential teratogenicity are resolved (407).

	VII. Summary and Perspectives

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 
Although dopamine is a small and relatively simple molecule, it fulfills many diverse functions. Within the brain, it acts as a classical neurotransmitter that exerts its actions within seconds. Yet, its attenuation or overactivity can lead to some of the most protractive neurological and psychological disorders. Within the pituitary, dopamine suppresses the high intrinsic secretory activity of lactotrophs. As this requires a continuous input of dopamine, the hypothalamic dopaminergic neurons differ from their striatal counterparts by being constitutively active. Acting via type 2 receptors that are functionally linked to membrane channels, dopamine rapidly inhibits PRL release from storage vesicles by controlling calcium fluxes. In addition, the G protein-linked receptor activates several interacting signaling pathways, resulting in the inhibition of PRL gene expression and the suppression of lactotroph proliferation. Although the mechanism of cell growth suppression by dopamine is not completely understood, this property has been exploited in the treatment of patients with prolactinomas and the restoration of their reproductive or neurological functions. In fact, the transfer of dopaminergic agonists/antagonists from the research bench to clinical practice and the generation of more effective and selective dopaminergic drugs is one of the most rewarding outcomes of basic research in this field.

The introduction of more refined detection and visualization techniques has been instrumental in attaining a more precise tracing of the hypothalamic dopaminergic pathways and a better delineation of their overlapping effects on pituitary function. Yet there remain several unresolved issues. For example, not all rises in PRL can be explained by reciprocal changes in dopamine production or secretion. Thus far, little is known about the relative importance and interactions between dopamine and a wide variety of compounds that stimulate PRL, generally known as PRFs. It remains a mystery whether there is a singular and predominant PRF, and if so, why 40 yr of research have failed in its isolation and identification.

Over the last decade, the field of dopamine-PRL interactions has advanced from a descriptive into a mechanistic phase. This has been aided by the cloning and characterization of the various receptors and transporters and the generation of transgenic animals with deleted or overexpressed genes that affect dopamine or PRL. However, because PRL is an adaptive hormone whose functions differ substantially among species, extrapolation of results obtained from transgenic mice should be done with caution. This is particularly true for the regulation and function of PRL in humans. For instance, knowledge of the role of PRL during human embryonic development is hampered by the lack of animal models with highly elevated PRL levels during pregnancy. Estrogen, known as a potent regulator of PRL secretion in rodents, has little acute effects on PRL in humans. Although some indirect evidence suggests that PRL is involved in immune regulation, mice with mutated PRL or PRL-R appear to have a normally functioning immune system. Whether this is true in other species, including humans, is presently unknown.

There are several areas in which future research may expand: 1) the mechanism underlying constitutive activation of the hypothalamic dopaminergic neurons and the hierarchy of their interactions with other neurotransmitters and neuropeptides; 2) the function of PRL as a neurotropic and survival factor for either the dopaminergic neurons or surrounding glia and the mechanism by which PRL is transported from the pituitary into the brain; 3) the origin and regulation of dopamine within the anterior pituitary; 4) the mechanism by which dopamine and its agonists inhibit lactotroph proliferation; and 5) the etiology of pituitary prolactinomas and the introduction of alternative treatments such as targeted gene therapy for their eradication.

	Acknowledgments

 
This work was supported by NIH Grants ES10154, ES09555, CA80920, National Science Foundation Grant IBN-9974848, and a grant from the Elsa U. Pardee Foundation.

	Footnotes

 
Abbreviations: AF, activator function; BPA, bisphenol A; CCK, cholecystokinin; CNS, central nervous system; COMT, catechol-O-methyl transferase; CSF, cerebrospinal fluid; DAT, dopamine transporter; DBD, DNA binding domain; DBH, dopamine ß-hydroxylase; DDC, L- aromatic amino acid decarboxylase; D₂L, D₂-type long isoform; DOPA, dihydroxyphenylalanine; DOPAC, dihydroxyphenylacetic acid; D₁R, D₁ receptor; D₂R, D₂ receptor; D₂S, D₂-type short isoform; ED, embryonic days; EGF, epidermal growth factor; eNOS, endothelial NO synthase; ERE, estrogen response element; GABA, -aminobutyric acid; GAT, GABA transporter; GRP, gastrin-related peptide; HBD, hormone binding domain; hGH, human GH; 5-HT, 5-hydroxytryptamine; JAK, Janus kinase; MAO, monoamine oxidase; MPP⁺, 1-methyl-4-phenylpyridinium; NGF, nerve growth factor; NO, nitric oxide; NSF, N-ethylmaleimide-sensitive factor; OP, octylphenol; OVEX, ovariectomized; PHDA, periventricular-hypophysial dopaminergic; PRF, PRL releasing factor; PRL-R, PRL receptor; SNAP, soluble NSF attachment proteins; SCN, suprachiasmatic nucleus; SNARE, SNAP receptors; stat, signal transducer and activator of transduction; TERPs, truncated ER products; TH, tyrosine hydroxylase; THDA, tuberohypophysial dopaminergic; TIDA, tuberoinfundibular dopaminergic; TM, transmembrane; TMD, TM domain; VEGF, vascular endothelial growth factor; VMAT, vesicular monoamine transporter.

	References

Top Abstract I. Introduction II. Characteristics of... III. The Hypothalamo-Pituitary... IV. Dopamine and the... V. Lessons Learned from... VI. Clinical Aspects VII. Summary and Perspectives References

 

1. Ben-Jonathan N 1985 Dopamine: a prolactin inhibiting hormone. Endocr Rev 6:564–589[Abstract/Free Full Text]
2. Nagatsu T, Stjarne L 1998 Catecholamine synthesis and release: overview. Adv Pharmacol 42:1–14
3. Fitzpatrick PF 2000 The aromatic amino acid hydroxylases. Adv Enzymol Relat Areas Mol Biol 74:235–294[CrossRef][Medline]
4. Nagatsu T, Ichinose H 1999 Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin. Mol Neurobiol 19:79–96[CrossRef][Medline]
5. Powell JF, Boni C, Lamouroux A, Craig IW, Mallet J 1984 Assignment of the human tyrosine hydroxylase gene to chromosome 11. FEBS Lett 175:37–40[CrossRef][Medline]
6. Kobayashi K, Morita S, Sawada H, Mizuguchi T, Yamada K, Nagatsu I, Hata T, Watanabe Y, Fujita K, Nagatsu T 1995 Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. J Biol Chem 270:27235–27243[Abstract/Free Full Text]
7. Kumer SC, Vrana KE 1996 Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem 67:443–462[Medline]
8. Godstein M 2000 Long- and short-term regulation of tyrosine hydroxylase. In: Meador-Woodruff JH, ed. Psychopharmacology. On-line ed., www.acnp.org. The American College of Psychoneuropharmacology; 1–6
9. Haycock JW, Haycock DA 1991 Tyrosine hydroxylase in rat brain dopaminergic nerve terminals: multiple-site phosphorylation in vivo and in synaptosomes. J Biol Chem 266:5650–5657[Abstract/Free Full Text]
10. Yang C, Kim HS, Seo H, Kim KS 1998 Identification and characterization of potential cis-regulatory elements governing transcriptional activation of the rat tyrosine hydroxylase gene. J Neurochem 71:1358–1368[Medline]
11. Tank AW, Piech KM, Osterhout CA, Sun B, Sterling C 1998 Regulation of tyrosine hydroxylase gene expression by transsynaptic mechanisms and cell-cell contact. Adv Pharmacol 42:25–29
12. Neff NH, Hadjiconstantinou M 1995 Aromatic L-amino acid decarboxylase modulation and Parkinson’s disease. Prog Brain Res 106:91–97[Medline]
13. Koller WC, Rueda MG 1998 Mechanism of action of dopaminergic agents in Parkinson’s disease. Neurology 50:S11–S14
14. Moore KE, Lookingland KJ 2000 Dopaminergic neuronal systems in the hypothalamus. In: Meador-Woodruff JH, ed. Psychopharmacology. On-line ed., www.acnp.org. The American College of Psychoneuropharmacology; 1–14
15. Boulton AA, Eisenhofer G 1998 Catecholamine metabolism. From molecular understanding to clinical diagnosis and treatment: overview. Adv Pharmacol 42:273–292
16. Shih JC, Chen K, Ridd MJ 1999 Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217[CrossRef][Medline]
17. Luque JM, Kwan SW, Abell CW, Da Prada M, Richards JG 1995 Cellular expression of mRNAs encoding monoamine oxidases A and B in the rat central nervous system. J Comp Neurol 363:665–680[CrossRef][Medline]
18. Betz WJ, Angleson JK 1998 The synaptic vesicle cycle. Annu Rev Physiol 60:347–363[CrossRef][Medline]
19. Langley K, Grant NJ 1997 Are exocytosis mechanisms neurotransmitter specific? Neurochem Int 31:739–757[CrossRef][Medline]
20. De Potter WP, Partoens P, Strecker S 1997 Noradrenaline storing vesicles in sympathetic neurons and their role in neurotransmitter release: an historical overview of controversial issues. Neurochem Res 22:911–919[CrossRef][Medline]
21. Brunger AT 2000 Structural insights into the molecular mechanism of Ca⁺⁺-dependent exocytosis. Curr Opin Neurobiol 10:293–302[CrossRef][Medline]
22. Millhorn DE, Hokfelt T 1988 Chemical messengers and their coexistence in individual neurons. News Physiol Sci 3:1–5[Abstract/Free Full Text]
23. Winkler H 1993 The adrenal chromaffin granule: a model for large dense core vesicles of endocrine and nervous tissue. J Anat 183:237–252
24. Payne CM 1989 Phylogenetic considerations of neurosecretory granule contents: role of nucleotides and basic hormone/transmitter packaging mechanisms. Arch Histol Cytol 52(Suppl):277–292
25. Hilfiker S, Pieribone VA, Czernik AJ, Kao HT, Augustine GJ, Greengard P 1999 Synapsins as regulators of neurotransmitter release. Philos Trans R Soc Lond B Biol Sci 354:269–279[Abstract/Free Full Text]
26. Marqueze B, Berton F, Seagar M 2000 Synaptotagmins in membrane traffic: which vesicles do the tagmins tag? Biochimie 82: 409–420
27. Klenchin VA, Martin TF 2000 Priming in exocytosis: attaining fusion-competence after vesicle docking. Biochimie 82:399–407[Medline]
28. Hodel A 1998 SNAP-25. Int J Biochem Cell Biol 30:1069–1073[CrossRef][Medline]
29. Mochida S 2000 Protein-protein interactions in neurotransmitter release. Neurosci Res 36:175–182[CrossRef][Medline]
30. Baumgarten HG, Bjorklund A, Holstein AF, Nobin A 1972 Organization and ultrastructural identification of the catecholamine nerve terminals in the neural lobe and pars intermedia of the rat pituitary. Z Zellforsch Mikrosk Anat 126:483–517[CrossRef][Medline]
31. Henry JP, Darchen F, Cribier S 1998 Physical techniques for the study of exocytosis in isolated cells. Biochimie 80:371–377[Medline]
32. Oberhauser AF, Fernandez JM 1996 A fusion pore phenotype in mast cells of the ruby-eye mouse. Proc Natl Acad Sci USA 93:14349–14354[Abstract/Free Full Text]
33. Bonisch H, Eiden L 1998 Catecholamine reuptake and storage: overview. Adv Pharmacol 42:149–164
34. Hoffman BJ, Hansson SR, Mezey E, Palkovits M 1998 Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front Neuroendocrinol 19:187–231[CrossRef][Medline]
35. Demarest KT, Moore KE 1979 Lack of a high affinity transport system for dopamine in the median eminence and posterior pituitary. Brain Res 171:545–551[CrossRef][Medline]
36. Blakely RD, Bauman AL 2000 Biogenic amine transporters: regulation in flux. Curr Opin Neurobiol 10:328–336[CrossRef][Medline]
37. Amara SG, Kuhar MJ 1993 Neurotransmitter transporters: recent progress. Annu Rev Neurosci 16:73–93[Medline]
38. Uhl GR, Johnson PS 1994 Neurotransmitter transporters: three important gene families for neuronal function. J Exp Biol 196: 229–236
39. Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP, Amara SG 1997 Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. J Neurosci 17:960–974[Abstract/Free Full Text]
40. Iversen L 2000 Neurotransmitter transporters: fruitful targets for CNS drug discovery. Mol Psychiatry 5:357–362[CrossRef][Medline]
41. Shimada S, Kitayama S, Lin CL, Patel A, Nanthakumar E, Gregor P, Kuhar M, Uhl G 1991 Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA. Science 254:576–578[Abstract/Free Full Text]
42. Usdin TB, Mezey E, Chen C, Brownstein MJ, Hoffman BJ 1991 Cloning of the cocaine-sensitive bovine dopamine transporter. Proc Natl Acad Sci USA 88:11168–11171[Abstract/Free Full Text]
43. Giros B, el Mestikawy S, Bertrand L, Caron MG 1991 Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett 295:149–154[CrossRef][Medline]
44. Giros B, el Mestikawy S, Godinot N, Zheng K, Han H, Yang-Feng T, Caron MG 1992 Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Mol Pharmacol 42:383–390[Abstract]
45. Sacchetti P, Brownschidle LA, Granneman JG, Bannon MJ 1999 Characterization of the 5'-flanking region of the human dopamine transporter gene. Brain Res Mol Brain Res 74:167–174[Medline]
46. Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T 1997 Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250[Abstract/Free Full Text]
47. Baffi JS, Palkovits M, Castillo SO, Mezey E, Nikodem VM 1999 Differential expression of tyrosine hydroxylase in catecholaminergic neurons of neonatal wild-type and Nurr1-deficient mice. Neuroscience 93:631–642[CrossRef][Medline]
48. Bannon MJ, Sacchetti P, Granneman JG 2000 The dopamine transporter: Potential involvement in neuropsychiatric disorders. In: Meador-Woodruff JH, ed. Psychopharmacology. On-line ed., www.acnp.org. The American College of Psychoneuropharmacology;1–11
49. Buck KJ, Lorang D, Amara SG 1996 Discrete structural domains and cell-specific expression determine functional selectivity of the dopamine and norepinephrine transporters. NIDA Res Monogr 161:154–175[Medline]
50. Giros B, Wang YM, Suter S, McLeskey SB, Pifl C, Caron MG 1994 Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters. J Biol Chem 269:15985–15988[Abstract/Free Full Text]
51. Vaughan RA, Huff RA, Uhl GR, Kuhar MJ 1997 Protein kinase C-mediated phosphorylation and functional regulation of dopamine transporters in striatal synaptosomes. J Biol Chem 272:15541–15546[Abstract/Free Full Text]
52. Ciliax BJ, Heilman C, Demchyshyn LL, Pristupa ZB, Ince E, Hersch SM, Niznik HB, Levey AI 1995 The dopamine transporter: immunochemical characterization and localization in brain. J Neurosci 15:1714–1723[Abstract]
53. Nirenberg MJ, Chan J, Pohorille A, Vaughan RA, Uhl GR, Kuhar MJ, Pickel VM 1997 The dopamine transporter: comparative ultrastructure of dopaminergic axons in limbic and motor compartments of the nucleus accumbens. J Neurosci 17:6899–6907[Abstract/Free Full Text]
54. Laruelle M 2000 Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20:423–451[Medline]
55. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG 1996 Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612[CrossRef][Medline]
56. Gasnier B 2000 The loading of neurotransmitters into synaptic vesicles. Biochimie 82:327–337[Medline]
57. Wang YM, Gainetdinov RR, Fumagalli F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG 1997 Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19:1285–1296
58. Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, Jackson-Lewis V, Przedborski S, Uhl GR 1997 VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci USA 94:9938–9943[Abstract/Free Full Text]
59. Fon EA, Pothos EN, Sun BC, Killeen N, Sulzer D, Edwards RH 1997 Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19:1271–1283[CrossRef][Medline]
60. Steiner-Mordoch S, Shirvan A, Schuldiner S 1996 Modification of the pH profile and tetrabenazine sensitivity of rat VMAT1 by replacement of aspartate 404 with glutamate. J Biol Chem 271:13048–13054[Abstract/Free Full Text]
61. Henry JP, Sagne C, Botton D, Isambert MF, Gasnier B 1998 Molecular pharmacology of the vesicular monoamine transporter. Adv Pharmacol 42:236–239
62. Kebabian JW, Calne DB 1979 Multiple receptors for dopamine. Nature 277:93–96[CrossRef][Medline]
63. Bunzow JR, Van Tol HH, Grandy DK, Albert P, Salon J, Christie M, Machida CA, Neve KA, Civelli O 1988 Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336:783–787[CrossRef][Medline]
64. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG 1998 Dopamine receptors: from structure to function. Physiol Rev 78:189–225[Abstract/Free Full Text]
65. Lachowicz JE, Sibley DR 1997 Molecular characteristics of mammalian dopamine receptors. Pharmacol Toxicol 81:105–113[Medline]
66. Ng GY, O’Dowd BF, Caron M, Dennis M, Brann MR, George SR 1994 Phosphorylation and palmitoylation of the human D2L dopamine receptor in Sf9 cells. J Neurochem 63:1589–1595[Medline]
67. Freedman NJ, Lefkowitz RJ 1996 Desensitization of G protein-coupled receptors. Recent Prog Horm Res 51:319–351
68. Simpson MM, Ballesteros JA, Chiappa V, Chen J, Suehiro M, Hartman DS, Godel T, Snyder LA, Sakmar TP, Javitch JA 1999 Dopamine D4/D2 receptor selectivity is determined by A divergent aromatic microdomain contained within the second, third, and seventh membrane-spanning segments. Mol Pharmacol 56:1116–1126[Abstract/Free Full Text]
69. Jaber M, Robinson SW, Missale C, Caron MG 1996 Dopamine receptors and brain function. Neuropharmacology 35:1503–1519[CrossRef][Medline]
70. O’Dowd BF 1993 Structures of dopamine receptors. J Neurochem 60:804–816[CrossRef][Medline]
71. Fryxell KJ 1995 The evolutionary divergence of neurotransmitter receptors and second-messenger pathways. J Mol Evol 41:85–97[Medline]
72. Guiramand J, Montmayeur JP, Ceraline J, Bhatia M, Borrelli E 1995 Alternative splicing of the dopamine D2 receptor directs specificity of coupling to G-proteins. J Biol Chem 270:7354–7358[Abstract/Free Full Text]
73. Mansour A, Meador-Woodruff JH, Bunzow JR, Civelli O, Akil H, Watson SJ 1990 Localization of dopamine D2 receptor mRNA and D1 and D2 receptor binding in the rat brain and pituitary: an in situ hybridization-receptor autoradiographic analysis. J Neurosci 10:2587–2600[Abstract]
74. O’Connell DP 1996 Expression of newly cloned brain dopamine receptors in peripheral organs. Biochem Soc Trans 24:169–172[Medline]
75. Seeman P 2000 Dopamine receptors: Clinical correlates. In: Meador-Woodruff JH, ed. Psychopharmacology. On-line ed., www.acnp.org. The American College of Psychoneuropharmacology; 1–12
76. Meltzer HY 1999 Treatment of schizophrenia and spectrum disorders: pharmacotherapy, psychosocial treatments, and neurotransmitter interactions. Biol Psychiatry 46:1321–1327[CrossRef][Medline]
77. Worrel JA, Marken PA, Beckman SE, Ruehter VL 2000 Atypical antipsychotic agents: a critical review. Am J Health Syst Pharm 57:238–255[Abstract/Free Full Text]
78. Picetti R, Saiardi A, Abdel ST, Bozzi Y, Baik JH, Borrelli E 1997 Dopamine D2 receptors in signal transduction and behavior. Crit Rev Neurobiol 11:121–142[Medline]
79. Caccavelli L, Cussac D, Pellegrini I, Audinot V, Jaquet P, Enjalbert A 1992 D2 dopaminergic receptors: normal and abnormal transduction mechanisms. Horm Res 38:78–83[Medline]
80. Sidhu A, Niznik HB 2000 Coupling of dopamine receptor subtypes to multiple and diverse G proteins. Int J Dev Neurosci 18:669–677[CrossRef][Medline]
81. Shafer RA, Levant B 1998 The D3 dopamine receptor in cellular and organismal function. Psychopharmacology (Berl) 135:1–16[CrossRef][Medline]
82. Goldstein M, Harada K, Meller E, Schalling M, Hokfelt T 1990 Dopamine autoreceptors. Biochemical, pharmacological, and morphological studies. Ann NY Acad Sci 604:169–175[CrossRef][Medline]
83. Durham RA, Eaton MJ, Moore KE, Lookingland KJ 1997 Effects of selective activation of dopamine D2 and D3 receptors on prolactin secretion and the activity of tuberoinfundibular dopamine neurons. Eur J Pharmacol 335:37–42[CrossRef][Medline]
84. Dahlstrom A, Fuxe K 1966 Monoamines and the pituitary gland. Acta Endocrinol 51:301–314
85. Kawano H, Daikoku S 1987 Functional topography of the rat hypothalamic dopamine neuron systems: retrograde tracing and immunohistochemical study. J Comp Neurol 265:242–253[CrossRef][Medline]
86. Goudreau JL, Falls WM, Lookingland KJ, Moore KE 1995 Periventricular-hypophysial dopaminergic neurons innervate the intermediate but not the neural lobe of the rat pituitary gland. Neuroendocrinology 62:147–154[Medline]
87. Meister B, Hokfelt T, Steinbusch HW, Skagerberg G, Lindvall O, Geffard M, Joh TH, Cuello AC, Goldstein M 1988 Do tyrosine hydroxylase-immunoreactive neurons in the ventrolateral arcuate nucleus produce dopamine or only L-dopa? J Chem Neuroanat 1:59–64[Medline]
88. Meister B, Elde R 1993 Dopamine transporter mRNA in neurons of the rat hypothalamus. Neuroendocrinology 58:388–395[Medline]
89. Chronwall BM, Millington WR, Griffin WST, Understall JR, O’Donohue TL 1987 Histological evaluation of the dopaminergic regulation of proopiomelanocortin gene expression in the intermediate lobe of the rat pituitary, involving in situ hybrodization and [³H]thymidine uptake measurement. Endocrinology 120:1201–1211[Abstract/Free Full Text]
90. Meunier H, Labrie F 1983 Multiple hormonal control of pars intermedia cell activity. Can J Biochem 61:516–531
91. Panayotacopoulou MT, Raadsheer FC, Swaab DF 1994 Colocalization of tyrosine hydroxylase with oxytocin or vasopressin in neurons of the human paraventricular and supraoptic nucleus. Brain Res Dev Brain Res 83:59–66[CrossRef][Medline]
92. Martignoni E, Horowski R, Liuzzi A, Costa A, Dallabonzana D, Cozzi R, Attanasio R, Rainer E, Nappi G 1996 Effects of terguride on anterior pituitary function in parkinsonian patients treated with L-dopa: a double-blind study vs. placebo. Clin Neuropharmacol 19:72–80[Medline]
93. Celio MR, Pasi A, Burgisser E, Buetti G, Hollt V, Gramsch Ch 1980 Proopiocortin fragments in normal human adult pituitary. Distribution and ultrastructural characterization of immunoreactive cells. Acta Endocrinol 95:27–40
94. Ugryumov MV 2000 The differentiation of dopaminergic neurons in situ, in vivo, and in transplants. Neurosci Behav Physiol 30:37–43[CrossRef][Medline]
95. Szabat E, Vanhatalo S, Soinila S 1998 The ontogenic appearance of tyrosine hydroxylase-, serotonin-, -aminobutyric acid-, calcitonin gene-related peptide-, substance P-, and synaptophysin- immunoreactivity in rat pituitary gland. Int J Dev Neurosci 16:449–460[CrossRef][Medline]
96. Coulon JF, Biguet NF, Cavoy A, Delacour J, Mallet J, David JC 1990 Gene expression of tyrosine hydroxylase in the developing fetal brain. J Neurochem 55:1412–1417[CrossRef][Medline]
97. Melnikova V, Orosco M, Calas A, Sapronova A, Gainetdinov R, Delhaye-Bouchaud N, Nicolaidis S, Rayevsky K, Ugrumov M 1999 Dopamine turnover in the mediobasal hypothalamus in rat fetuses. Neuroscience 89:235–241[CrossRef][Medline]
98. Arbogast LA, Voogt JL 1997 Prolactin (PRL) receptors are colocalized in dopaminergic neurons in fetal hypothalamic cell cultures: effect of PRL on tyrosine hydroxylase activity. Endocrinology 138:3016–3023[Abstract/Free Full Text]
99. Balan IS, Ugrumov MV, Calas A, Mailly P, Krieger M, Thibault J 2000 Tyrosine hydroxylase-expressing and/or aromatic L-amino acid decarboxylase-expressing neurons in the mediobasal hypothalamus of perinatal rats: differentiation and sexual dimorphism. J Comp Neurol 425:167–176[CrossRef][Medline]
100. Beyer C, Pilgrim C, Reisert I 1991 Dopamine content and metabolism in mesencephalic and diencephalic cell cultures: sex differences and effects of sex steroids. J Neurosci 11:1325–1333[Abstract]
101. Gary KA, Chronwall BM 1992 The onset of dopaminergic innervation during ontogeny decreases melanotrope proliferation in the intermediate lobe of the rat pituitary. Int J Dev Neuroscience 10:131–142[CrossRef][Medline]
102. Loudes C, Petit F, Kordon C, Faivre-Bauman A 1999 Distinct populations of hypothalamic dopaminergic neurons exhibit differential responses to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). Eur J Neurosci 11:617–624[CrossRef][Medline]
103. Loudes C, Rougon G, Kordon C, Faivre-Bauman A 1997 Polysialylated neural cell adhesion is involved in target-induced morphological differentiation of arcuate dopaminergic neurons. Eur J Neurosci 9:2323–2333[CrossRef][Medline]
104. Davis MD, Lichtensteiger W, Schlumpf M, Bruinink A 1984 Early postnatal development of pituitary intermediate lobe control in the rat by dopamine neurons. Neuroendocrinology 39:1–12[Medline]
105. Freeman ME, Kanyicska B, Lerant A, Nagy G 2000 Prolactin: structure, function, and regulation of secretion. Physiol Rev 80:1523–1631[Abstract/Free Full Text]
106. Arbogast LA, Ben-Jonathan N 1989 Tyrosine hydroxylase in the stalk-median eminence and posterior pituitary is inactivated only during the plateau phase of the preovulatory prolactin surge. Endocrinology 125:667–674[Abstract/Free Full Text]
107. Arbogast LA, Voogt JL 1991 Mechanisms of tyrosine hydroxylase regulation during pregnancy: Evidence for protein dephosphorylation during the prolactin surges. Endocrinology 129:2575–2582[Abstract/Free Full Text]
108. Pasqualini C, Guibert B, Leviel V 1993 Short-term inhibitory effect of estradiol on tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons in vitro. J Neurochem 60:1707–1713[Medline]
109. Annunziato L, Leblanc P, Kordon C, Weiner RI 1980 Differences in the kinetics of dopamine uptake in synaptosome preparations of the median eminence relative to other dopaminergically innervated brain regions. Neuroendocrinology 31:316–320[Medline]
110. Garris PA, Ben-Jonathan N 1991 Effects of reuptake inhibitors on dopamine release from the stalk-median eminence and posterior pituitary in vitro. Brain Res 556:123–129[CrossRef][Medline]
111. Demaria JE, Nagy GM, Lerant AA, Fekete MI, Levenson CW, Freeman ME 2000 Dopamine transporters participate in the physiological regulation of prolactin. Endocrinology 141:366–374[Abstract/Free Full Text]
112. Bosse R, Fumagalli F, Jaber M, Giros B, Gainetdinov RR, Wetsel WC, Missale C, Caron MG 1997 Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter. Neuron 19:127–138[CrossRef][Medline]
113. Pan J-T 1996 Neuroendocrine functions of dopamine. In: Stone TW, ed. CNS neurotransmitters and neuromodulators: dopamine. Boca Raton, FL: CRC Press; 213–231
114. Manzanares J, Wagner EJ, LaVigne SD, Lookingland KJ, Moore KE 1992 Sexual differences in opioid receptor-mediated regulation of tuberoinfundibular dopaminergic neurons. Neuroendocrinology 55:301–307[Medline]
115. Toney TW, Manzanares J, Moore KE, Lookingland KJ 1992 Sexual differences in the stimulatory effects of bombesin on tuberoinfundibular dopaminergic neurons. Brain Res 598:279–285[CrossRef][Medline]
116. Moore KE, Demarest KT, Lookingland KJ 1987 Stress, prolactin and hypothalamic dopaminergic neurons. Neuropharmacology 26:801–808[CrossRef][Medline]
117. Lerant A, Freeman ME 1997 Dopaminergic neurons in periventricular and arcuate nuclei of proestrous and ovariectomized rats: endogenous diurnal rhythm of Fos-related antigens expression. Neuroendocrinology 65:436–445[Medline]
118. Lerant A, Herman ME, Freeman ME 1996 Dopaminergic neurons of periventricular and arcuate nuclei of pseudopregnant rats: semicircadian rhythm in Fos-related antigens immunoreactivities and in dopamine concentration. Endocrinology 137:3621–3628[Abstract]
119. Yen SH, Pan JT 1998 Progesterone advances the diurnal rhythm of tuberoinfundibular dopaminergic neuronal activity and the prolactin surge in ovariectomized, estrogen-primed rats and in intact proestrous rats. Endocrinology 139:1602–1609[Abstract/Free Full Text]
120. Yen SH, Pan JT 1999 Nitric oxide plays an important role in the diurnal change of tuberoinfundibular dopaminergic neuronal activity and prolactin secretion in ovariectomized, estrogen/progesterone-treated rats. Endocrinology 140:286–291[Abstract/Free Full Text]
121. Demaria JE, Livingstone JD, Freeman ME 1998 Characterization of the dopaminergic input to the pituitary gland throughout the estrous cycle of the rat. Neuroendocrinology 67:377–383[CrossRef][Medline]
122. Demaria JE, Livingstone JD, Freeman ME 2000 Ovarian steroids influence the activity of neuroendocrine dopaminergic neurons. Brain Res 879:139–147[CrossRef][Medline]
123. Demaria JE, Lerant A, Freeman ME 1999 Prolactin activates all three populations of hypothalamic neuroendocrine dopaminergic neurons in ovariectomized rats. Brain Res 837:236–241[CrossRef][Medline]
124. Peters LL, Hoefer MT, Ben-Jonathan N 1981 The posterior pituitary: regulation of anterior pituitary prolactin secretion. Science 213:659–661[Abstract/Free Full Text]
125. Froehlich JC, Ben-Jonathan N 1984 Posterior pituitary involvement in the control of luteinizing hormone and prolactin secretion during the estrous cycle. Endocrinology 114:1059–1064[Abstract/Free Full Text]
126. Demaria JE, Zelena D, Vecsernyes M, Nagy GM, Freeman ME 1998 The effect of neurointermediate lobe denervation on hypothalamic neuroendocrine dopaminergic neurons. Brain Res 806:98–94
127. Ben-Jonathan N 1990 Prolactin releasing and inhibiting factors in the posterior pituitary. In: MacLeod RM, Muller EE, eds. Neuroendocrine Perspectives. New York: Springer-Verlag; 1–38
128. Durham RA, Johnson JD, Eaton MJ, Moore KE, Lookingland KJ 1998 Opposing roles for dopamine D1 and D2 receptors in the regulation of hypothalamic tuberoinfundibular dopamine neurons. Eur J Pharmacol 355:141–147[CrossRef][Medline]
129. Gunnet JW, Moore KE 1988 Neuroleptics and neuroendocrine function. Annu Rev Pharmacol Toxicol 28:347–366[CrossRef][Medline]
130. Durham RA, Johnson JD, Moore KE, Lookingland KJ 1996 Evidence that D2 receptor-mediated activation of hypothalamic tuberoinfundibular dopaminergic neurons in the male rat occurs via inhibition of tonically active afferent dynorphinergic neurons. Brain Res 732:113–120[CrossRef][Medline]
131. Lamberts SWJ, MacLeod RM 1990 Regulation of prolactin secretion at the level of the lactotroph. Physiol Rev 70:279–318[Free Full Text]
132. Hentschel K, Moore KE, Lookingland KJ 2000 Effects of prolactin on expression of Fos-related antigens in tyrosine hydroxylase-immunoreactive neurons in subdivisions of the arcuate nucleus. Brain Res 857:110–118[CrossRef][Medline]
133. Sagrillo CA, Selmanoff M 1998 Effects of prolactin on expression of the mRNAs encoding the immediate early genes zif/268 (NGF1-A), nur/77 (NGF1-B), c-fos and c-jun in the hypothalamus. Brain Res Mol Brain Res 61:62–68[Medline]
134. Emanuele NV, Jurgens JK, Halloran MM, Tentler JJ, Lawrence AM, Kelly MR 1992 The rat prolactin gene is expressed in brain tissue: dectection of normal and alternatively spliced prolactin messenger RNA. Mol Endocrinol 6:35–42[Abstract/Free Full Text]
135. DeVito WJ, Avakian C, Stone S, Ace C 1992 Estradiol increases prolactin synthesis and prolactin messenger ribonucleic acid in selected brain regions in the hypophysectomized female rat. Endocrinology 131:2154–2160[Abstract/Free Full Text]
136. Mangurian LP, Walsh RJ, Posner BI 1992 Prolactin enhancement of its own uptake at the choroid plexus. Endocrinology 131:698–702[Abstract/Free Full Text]
137. Brooks PJ, Funabashi T, Kleopoulos SP, Mobbs CV, Pfaff DW 1992 Prolactin receptor messenger RNA is synthesized by the epithelial cells of the choroid plexus. Brain Res Mol Brain Res 16:163–167[Medline]
138. Di Carlo R, Muccioli G, Papotti M, Bussolati G 1992 Characterization of prolactin receptor in human brain and choroid plexus. Brain Res 570:341–346[CrossRef][Medline]
139. DeVito WJ, Avakian C, Stone S, Okulicz WC 1993 Prolactin-stimulated mitogenesis of cultured astrocytes is mediated by a protein kinase C-dependent mechanism. J Neurochem 60:835–842[CrossRef]
140. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA 1998 Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 19:225–268[Abstract/Free Full Text]
141. Goffin V, Binart N, Clement-Lacroix P, Bouchard B, Bole-Feysot C, Edery M, Lucas BK, Touraine P, Pezet A, Maaskant R, Pichard C, Helloco C, Baran N, Favre H, Bernichtein S, Allamando A, Ormandy C, Kelly PA 1999 From the molecular biology of prolactin and its receptor to the lessons learned from knockout mice models. Genet Anal 15:189–201[Medline]
142. Hu Z-Z, Zhuang L, Dufau ML 1998 Prolactin receptor gene diversity: structure and regulation. Trend Endocrinol Metab 9:94–102[CrossRef][Medline]
143. Horseman ND, Yu-Lee LY 1994 Transcriptional regulation by the helix bundle peptide hormones: growth hormone, prolactin, and hematopoietic cytokines. Endocr Rev 15:627–649[Abstract/Free Full Text]
144. Nagano M, Kelly PA 1994 Tissue distribution and regulation of rat prolactin receptor gene expression. J Biol Chem 269:13337–13345[Abstract/Free Full Text]
145. Ali S, Pellegrini I, Kelly PA 1991 A prolactin-dependent immune cell line (Nb2) expresses a mutant form of prolactin receptor. J Biol Chem 266:20110–20117[Abstract/Free Full Text]
146. Postel-Vinay MC, Belair L, Kayser C, Kelly PA, Djiane J 1991 Identification of prolactin and growth hormone binding proteins in rabbit milk. Proc Nat Acad Sci USA 88:6687–6690[Abstract/Free Full Text]
147. Arden KC, Boutin JM, Djiane J, Kelly PA, Cavenee WK 1990 The receptors for prolactin and growth hormone are localized in the same region of human chromosome 5. Cytogenet Cell Genet 53:161–165[Medline]
148. Kline JB, Roehrs H, Clevenger CV 1999 Functional characterization of the intermediate isoform of the human prolactin receptor. J Biol Chem 274:35461–35468[Abstract/Free Full Text]
149. Sakal E, Elberg G, Gertler A 1997 Direct evidence that lactogenic hormones induce homodimerization of membrane-anchored prolactin receptor in intact Nb2–11C rat lymphoma cells. FEBS Lett 410:289–292[CrossRef][Medline]
150. Clevenger CV, Altmann SW, Prystowsky MB 1991 Requirement of nuclear prolactin for interleukin-2-stimulated proliferation of T lymphocytes. Science 253:77–80[Abstract/Free Full Text]
151. Perrot-Applanat M, Gualillo O, Buteau H, Edery M, Kelly PA 1997 Internalization of prolactin receptor and prolactin in transfected cells does not involve nuclear translocation. J Cell Sci 110:1123–1132[Abstract]
152. Lai Z, Zhai Q, Liu Z, Roos P, Nyberg F 1995 Morphine-induced prolactin release precedes a down-regulation of prolactin receptors in the male rat choroid plexus and hypothalamus. Neurosci Res 23:313–316[CrossRef][Medline]
153. Maaskant RA, Bogic LV, Gilger S, Kelly PA, Bryant-Greenwood GD 1996 The human prolactin receptor in the fetal membranes, decidua, and placenta. J Clin Endocrinol Metab 81:369–405
154. Mercado M, Baumann G 1994 A growth hormone/prolactin-binding protein in human milk. J Clin Endocrinol Metab 79:1637–1641[Abstract]
155. Hennighausen L, Robinson GW, Wagner KU, Liu X 1997 Developing a mammary gland is a stat affair. J Mammary Gland Biol Neoplasia 2:365–372[CrossRef][Medline]
156. Muccioli G, Ghe C, Di Carlo R 1991 Distribution and characterization of prolactin binding sites in the male and female rat brain: effects of hypophysectomy and ovariectomy. Neuroendocrinology 53:47–53[Medline]
157. Lerant A, Freeman ME 1998 Ovarian steroids differentially regulate the expression of PRL-R in neuroendocrine dopaminergic neuron populations: a double label confocal microscopic study. Brain Res 802:141–154[CrossRef][Medline]
158. Pi XJ, Grattan DR 1999 Increased expression of both short and long forms of prolactin receptor mRNA in hypothalamic nuclei of lactating rats. J Mol Endocrinol 23:13–22[Abstract]
159. Sakaguchi K, Tanaka M, Ohkubo T, Doh-ura K, Fujikawa T, Sudo S, Nakashima K 1996 Induction of brain prolactin receptor long-form mRNA expression and maternal behavior in pup-contacted male rats: promotion by prolactin administration and suppression by female contact. Neuroendocrinology 63:559–568[Medline]
160. Sugiyama T, Minoura H, Toyoda N, Sakaguchi K, Tanaka M, Sudo S, Nakashima K 1996 Pup contact induces the expression of long form prolactin receptor mRNA in the brain of female rats: effects of ovariectomy and hypophysectomy on receptor gene expression. J Endocrinol 149:335–340[Abstract/Free Full Text]
161. Chiu S, Wise PM 1996 Prolactin receptor gene expression in specific hypothalamic nuclei increases with age. J Gerontol A Biol Sci Med Sci 51:B220–B224
162. Pi XJ, Grattan DR 1999 Increased prolactin receptor immunoreactivity in the hypothalamus of lactating rats. J Neuroendocrinol 11:693–705[CrossRef][Medline]
163. Pasqualini C, Bojda F, Gaudoux F, Guibert B, Leviel V, Teissier E, Rips R, Kerdelhue B 1988 Changes in tuberoinfundibular dopaminergic neuron activity during the rat estrous cycle in relation to the prolactin surge: alteration by a mammary carcinogen. Neuroendocrinology 48:320–327[CrossRef][Medline]
164. Arbogast LA, Voogt JL 1991 Hyperprolactinemia increases and hypoprolactinemia decreases tyrosine hydroxylase messenger ribonucleic acid levels in the arcuate nuclei, but not the substantia nigra or zona incerta. Endocrinology 128:997–1005[Abstract/Free Full Text]
165. Gonzalez HA, Porter JC 1988 Mass and in situ activity of tyrosine hydroxylase in the median eminence: effect of hyperprolactinemia. Endocrinology 122:2272–2277[Abstract/Free Full Text]
166. Demaria JE, Nagy GM, Freeman ME 2000 Immunoneutralization of prolactin prevents stimulatory feedback of prolactin on hypothalamic neuroendocrine dopaminergic neurons. Endocrine 12:333–337[CrossRef][Medline]
167. Hentschel K, Fleckenstein AE, Toney TW, Lawson DM, Moore KE, Lookingland KJ 2000 Prolactin regulation of tuberoinfundibular dopaminergic neurons: immuno-neutralization studies. Brain Res 852:28–36[CrossRef][Medline]
168. Arbogast LA, Voogt JL 1996 The responsiveness of Tuberoinfundibular dopaminergic nuerons to prolactin feedback is diminished between early lactation and midlactation the rat. Endocrinology 137:47–54[Abstract]
169. Li S, Crenshaw III EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG 1999 Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 347:528–533
170. Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, O’conell SM, Gukovsky I, Carriere C, Ryan AK, Miller AP, Zuo L, Gleiberman AS, Anderson B, Beamer WG, Rosenfeld MG 1996 Pituitary lineage of the prophete of pit-1 homeodomain factor defective in Ames dwarfism. Nature 384:327–333[CrossRef][Medline]
171. Morgan WW, Bartke A, Pfeil K 1981 Deficiency of dopamine in the median eminence of Snell dwarf mice. Endocrinology 109:2069–2075[Abstract/Free Full Text]
172. Phelps C 1994 Pituitary hormones as neurotropic signals: Anomalous hypophysiotrophic neuron differentiation in hypopituitary dwarf mice. Proc Soc Exp Biol Med 206:6–23[CrossRef][Medline]
173. Grosvenor CE, Whitworth NS 1983 Accumulation of prolactin in maternal milk and its transfer to circulation of neonate rat: a review. Endocrinol Exp 17:271–282[Medline]
174. Vonderhaar BK 1999 Prolactin involvement in breast cancer. Endocr Relat Cancer 6:389–404[Abstract]
175. Clevenger CV, Plank TL 1997 Prolactin as an autocrine/paracrine factor in breast tissue. J Mammary Gland Biol Neoplasia 2:59–68[CrossRef][Medline]
176. Dorshkind K, Horseman ND 2000 The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency. Endocr Rev 21:292–312[Abstract/Free Full Text]
177. DeVito WJ, Avakian C, Stone S, Okulicz WC, Tang KT, Shamgochian M 1995 Prolactin induced expression of interleukin-1, tumor necrosis factor- and transforming growth factor- in cultured astrocytes. J Cell Biochem 57:290–298[CrossRef][Medline]
178. DeVito WJ, Stone S 1999 Ethanol inhibits prolactin-induced activation of the JAK/STAT pathway in cultured astrocytes. J Cell Biochem 74:278–291[CrossRef][Medline]
179. Mangoura D, Pelletiere C, Leung S, Sakellaridis N, Wang DX 2000 Prolactin concurrently activates src-PLD and JAK/Stat signaling pathways to induce proliferation while promoting differentiation in embryonic astrocytes. Int J Dev Neurosci 18:693–704[CrossRef][Medline]
180. Arbogast LA, Hyde JF 2000 Estradiol attenuates the forskolin-induced increase in hypothalamic tyrosine hydroxylase activity. Neuroendocrinology 71:219–227[CrossRef][Medline]
181. Kohama SG, Bethea CL 1995 Steroid regulation of tyrosine hydroxylase messenger ribonucleic acid in dopaminergic subpopulations if monkey hypothalamus. Endocrinology 136:1790–1800[Abstract]
182. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L 1996 Nuclear receptor coactivators and corepressors. Mol Endocrinol 10:1167–1177[Abstract/Free Full Text]
183. Katzenellenbogen JA, O’Malley BW, Katzenellenbogen BS 1996 Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. Mol Endocrinol 10:119–131[Free Full Text]
184. Gustafsson JA 2000 An update on estrogen receptors. Semin Perinatol 24:66–69[CrossRef][Medline]
185. Beato M, Klug J 2000 Steroid hormone receptors: an update. Hum Reprod Update 6:225–236[Abstract/Free Full Text]
186. Maalouf GJ, Xu W, Smith TF, Mohr SC 1998 Homology model for the ligand-binding domain of the human estrogen receptor. J Biomol Struct Dyn 15:841–851[Medline]
187. Freedman LP, Luisi BF 1993 On the mechanism of DNA binding by nuclear hormone receptors: a structural and functional perspective. J Cell Biochem 51:140–150[CrossRef][Medline]
188. Parker MG 1998 Transcriptional activation by oestrogen receptors. Biochem Soc Symp 63:45–50[Medline]
189. Klinge CM 2000 Estrogen receptor interaction with co-activators and co-repressors. Steroids 65:227–251[CrossRef][Medline]
190. Stancel GM, Boettger-Tong HL, Chiappetta C, Hyder SM, Kirkland JL, Murthy L, Loose-Mitchell DS 1995 Toxicity of endogenous and environmental estrogens: what is the role of elemental interactions? Environ Health Perspect 103(Suppl 7):29–33
191. Dechering K, Boersma C, Mosselman S 2000 Estrogen receptors and ß: two receptors of a kind? Curr Med Chem 7:561–576[Medline]
192. Petersen DN, Tkalcevic GT, Koza-Taylor PH, Turi TG, Brown TA 1998 Identification of estrogen receptor ß2, a functional variant of estrogen receptor ß expressed in normal rat tissues. Endocrinology 139:1082–1092[Abstract/Free Full Text]
193. Pace P, Taylor J, Suntharalingam S, Coombes RC, Ali S 1997 Human estrogen receptor ß binds DNA in a manner similar to and dimerizes with estrogen receptor . J Biol Chem 272:25832–25838[Abstract/Free Full Text]
194. Kuiper GG, Shughrue PJ, Merchenthaler I, Gustafsson JA 1998 The estrogen receptor ß subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroendocrinol 19: 253–286
195. Nishihara E, Nagayama Y, Inoue S, Hiroi H, Muramatsu M, Yamashita S, Koji T 2000 Ontogenetic changes in the expression of estrogen receptor and ß in rat pituitary gland detected by immunohistochemistry. Endocrinology 141:615–620[Abstract/Free Full Text]
196. Mitchner NA, Garlick C, Ben-Jonathan N 1998 Cellular distribution and gene regulation of estrogen receptors and ß in the rat pituitary gland. Endocrinology 139:3976–3983[Abstract/Free Full Text]
197. Couse JF, Lindzey J, Grandien K, Gustafsson J-A, Korach KS 1997 Tissue distribution and quantitative analysis of estrogen receptor- (ER) and estrogen receptor-ß (ERß) messenger ribonucleic acid in the wild-type and ER-knockout mouse. Endocrinology 138:4613–4621[Abstract/Free Full Text]
198. Resnick EM, Schreihofer DA, Periasamy A, Shupnik MA 2000 Truncated estrogen receptor product-1 suppresses estrogen receptor transactivation by dimerization with estrogen receptors and ß. J Biol Chem 275:7158–7166[Abstract/Free Full Text]
199. Shughrue PJ, Lane MV, Merchenthaler I 1997 Comparative distribution of estrogen receptor- and -ß mRNA in the rat central nervous system. J Comp Neurol 388:507–525[CrossRef][Medline]
200. Arbogast LA, Ben-Jonathan N 1988 The preovulatory prolactin surge: an evaluation of the role of dopamine. Endocrinology 123:2690–2695[Abstract/Free Full Text]
201. Arbogast LA, Murai I, Ben-Jonathan N 1989 Differential alterations in dopamine turnover rates in the stalk-median eminence and posterior pituitary during the preovulatory prolactin surge. Neuroendocrinology 49:525–530[Medline]
202. Arbogast LA, Voogt JL 1993 Progesterone reverses the estradiol-induced decrease in tyrosine hydroxylase mRNA levels in the arcuate nucleus. Neuroendocrinology 58:501–510[Medline]
203. Arbogast LA, Voogt JL 1994 Progesterone suppresses tyrosine hydroxylase messenger ribonucleic acid levels in the arcuate nucleus on proestrus. Endocrinology 135:343–350[Abstract]
204. Ben-Jonathan N, Steinmetz R 1998 Xenoestrogens: the emerging story of bisphenol A. Trend Endocrinol Metab 9:124–128[CrossRef][Medline]
205. Katzenellenbogen JA 1995 The structural pervasiveness of estrogenic activity. Environ Health Perspect 103:99–101
206. Colborn T 1995 Environmental estrogens: health implications for humans and wildlife. Environ Health Perspect 103:135–136
207. Steinmetz R, Brown NG, Allen DL, Bigsby RM, Ben-Jonathan N 1997 The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology 138:1780–1786[Abstract/Free Full Text]
208. Chun TY, Gorski J 2000 High concentrations of bisphenol A induce cell growth and prolactin secretion in an estrogen-responsive pituitary tumor cell line. Toxicol Appl Pharmacol 162:161–165[CrossRef][Medline]
209. Abraham EJ, Frawley LS 1997 Octylphenol (OP), an environmental estrogen, stimulates prolactin (PRL) gene expression. Life Sci 60:1457–1465[CrossRef][Medline]
210. Khurana S, Ranmal S, Ben-Jonathan N 2000 Exposure of newborn male and female rats to environmental estrogens: delayed and sustained hyperprolactinemia and alterations in estrogen receptor expression. Endocrinology 141:4512–4517[Abstract/Free Full Text]
211. Russell KS, Haynes MP, Sinha D, Clerisme E, Bender JR 2000 Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. Proc Natl Acad Sci USA 97:5930–5935[Abstract/Free Full Text]
212. Stefano GB, Prevot V, Beauvillain JC, Cadet P, Fimiani C, Welters I, Fricchione GL, Breton C, Lassalle P, Salzet M, Bilfinger TV 2000 Cell surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia. Circulation 101:1594–1597[Abstract/Free Full Text]
213. Russell KS, Haynes MP, Caulin-Glaser T, Rosneck J, Sessa WC, Bender JR 2000 Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells. Effects on calcium sensitivity and NO release. J Biol Chem 275:5026–5030[Abstract/Free Full Text]
214. Goetz RM, Thatte HS, Prabhakar P, Cho MR, Michel T, Golan DE 1999 Estradiol induces the calcium-dependent translocation of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 96:2788–2793[Abstract/Free Full Text]
215. Prevot V, Croix D, Rialas CM, Poulain P, Fricchione GL, Stefano GB, Beauvillain JC 1999 Estradiol coupling to endothelial nitric oxide stimulates gonadotropin-releasing hormone release from rat median eminence via a membrane receptor. Endocrinology 140:652–659[Abstract/Free Full Text]
216. Garris PA, Ben-Jonathan N 1991 Estradiol rapidly stimulates dopamine release from the posterior pituitary in vitro via an opioidergic mechanism. Neuroendocrinology 53:601–607[Medline]
217. Moss RL, Gu Q 1999 Estrogen: mechanisms for a rapid action in CA1 hippocampal neurons. Steroids 64:14–21[CrossRef][Medline]
218. Watters JJ, Campbell JS, Cunningham MJ, Krebs EG, Dorsa DM 1997 Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. Endocrinology 138:4030–4033[Abstract/Free Full Text]
219. Watson CS, Norfleet AM, Pappas TC, Gametchu B 1999 Rapid actions of estrogens in GH3/B6 pituitary tumor cells via a plasma membrane version of estrogen receptor . Steroids 64:5–13[CrossRef][Medline]
220. Watters JJ, Chun TY, Kim YN, Bertics PJ, Gorski J 2000 Estrogen modulation of prolactin gene expression requires an intact mitogen-activated protein kinase signal transduction pathway in cultured rat pituitary cells. Mol Endocrinol 14:1872–1881[Abstract/Free Full Text]
221. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW 1999 Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 103:401–406[Medline]
222. Watson CS, Campbell CH, Gametchu B 1999 Membrane oestrogen receptors on rat pituitary tumour cells: immuno-identification and responses to oestradiol and xenoestrogens. Exp Physiol 84:1013–1022[Abstract]
223. Kim HP, Lee JY, Jeong JK, Bae SW, Lee HK, Jo I 1999 Nongenomic stimulation of nitric oxide release by estrogen is mediated by estrogen receptor localized in caveolae. Biochem Biophys Res Commun 263:257–262[CrossRef][Medline]
224. Shaul PW, Anderson RG 1998 Role of plasmalemmal caveolae in signal transduction. Am J Physiol 275:L843–L851
225. Connor M, Christie MD 1999 Opioid receptor signalling mechanisms. Clin Exp Pharmacol Physiol 26:493–499[CrossRef][Medline]
226. Horvath TL, Naftolin F, Leranth C 1992 B-endorphin innervation of dopamine neurons in the rat hypothalamus: a light and electron microscopic double immunostaining study. Endocrinology 131:1547–1555[Abstract/Free Full Text]
227. Mansour A, Fox CA, Akil H, Watson SJ 1995 Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18:22–29[CrossRef][Medline]
228. Fitzsimmons MD, Olschowka JA, Wiegand SJ, Hoffman GE 1992 Interaction of opioid peptide-containing terminals with dopaminergic perikarya in the rat hypothalamus. Brain Res 581:10–18[CrossRef][Medline]
229. Day R, Schafer MK, Collard MW, Weihe E, Akil H 1993 Prodynorphin gene expression in the rat intermediate pituitary lobe: gender differences and postpartum regulation. Endocrinology 133:2652–2659[Abstract/Free Full Text]
230. Callahan P, Klosterman S, Prunty D, Tompkins J, Janik J 2000 Immuno-neutralization of endogenous opioid peptides prevents the suckling-induced prolactin increase and the inhibition of tuberoinfundibular dopaminergic neurons. Neuroendocrinology 71:268–276[CrossRef][Medline]
231. Garris PA, Ben-Jonathan N 1990 Regulation of dopamine release in vitro from the posterior pituitary by opioid peptides. Neuroendocrinology 52:399–404[Medline]
232. Loose MD, Ronnekleiv OK, Kelly MJ 1990 Membrane properties and response to opioids in identified dopmaine neurons in the guinea pig hypothalamus. J Neurosci 10:3627–3634[Abstract]
233. Lin JY, Pan JT 1995 Effects of endogenous opioid peptides and their analogs on the activities of hypothalamic arcuate neurons in brain slices from diestrous and ovariectomized rats. Brain Res Bull 36:225–233[CrossRef][Medline]
234. Arita J, Kimura F 1988 Enkephalin inhibits dopamine synthesis in vitro in the median eminence portion of rat hypothalamic slices. Endocrinology 123:694–699[Abstract/Free Full Text]
235. Ieiri T, Chen HT, Campbell GA, Meites J 1980 Effects of naloxone and morphine on the proestrous surge of prolactin and gonadotropins in the rat. Endocrinology 106:1568–1570[Abstract/Free Full Text]
236. Hou Y, Voogt JL 1999 Effects of naloxone infusion on nocturnal prolactin secretion and Fos/FRA expression in pregnant rats. Endocrine 10:145–152[CrossRef][Medline]
237. Arbogast LA, Voogt JL 1998 Endogenous opioid peptides contribute to suckling-induced prolactin release by suppressing tyrosine hydroxylase activity and messenger ribonucleic acid levels in tuberoinfundibular dopaminergic neurons. Endocrinology 139:2857–2862[Abstract/Free Full Text]
238. Petraglia F, Vale W, Rivier C 1987 ß-Endorphin and dynorphin participate in the stress-induced release of prolactin in the rat. Neuroendocrinology 45:338–342[Medline]
239. Wank SA, Pisegna JR, de Weerth A 1994 Cholecystokinin receptor family. Molecular cloning, structure, and functional expression in rat, guinea pig, and human. Ann NY Acad Sci 713:49–66[Medline]
240. Ciofi P, Tramu G 1985 Demonstration of gastrin/cholecystokinin-like immunoreactivity in the arcuate nucleus, median eminence and pituitary of the guinea pig. Neurosci Lett 62:293–298[CrossRef][Medline]
241. Tanimoto K, Tamminga CA, Chase TN, Nilaver G 1987 Intracerebroventricular injection of cholecystokinin octapeptide elevates plasma prolactin levels through stimulation of vasoactive intestinal polypeptide. Endocrinology 121:127–132[Abstract/Free Full Text]
242. Vijayan E, McCann SM 1987 The effects of the cholecystokinin antagonist, proglumide, on prolactin secretion in the rat. Life Sci 40:629–634[CrossRef][Medline]
243. Lin JY, Li CS, Pan JT 1993 Effects of various neuroactive substances on single-unit activities of hypothalamic arcuate neurons in brain slices. Brain Res Bull 31:587–594[CrossRef][Medline]
244. Romijn HJ, Sluiter AA, Pool CW, Wortel J, Buijs RM 1997 Evidence from confocal fluorescence microscopy for a dense, reciprocal innervation between AVP-, somatostatin-, VIP/PHI-, GRP-, and VIP/PHI/GRP-immunoreactive neurons in the rat suprachiasmatic nucleus. Eur J Neurosci 9:2613–2623[CrossRef][Medline]
245. Lin JY, Pan JT 1994 Stimulatory effects of bombesin-like peptides on hypothalamic arcuate neurons in rat brain slices. Brain Res Bull 35:241–246[CrossRef][Medline]
246. Mai LM, Pan JT 1995 Bombesin acts in the suprachiasmatic nucleus to affect circadian changes in tuberoinfundibular dopaminergic neuron activity and prolactin secretion. Endocrinology 136:4163–4167[Abstract]
247. Kentroti S, Dees WL, McCann SM 1988 Evidence for a physiological role of hypothalamic gastrin-releasing peptide to suppress growth hormone and prolactin release in the rat. Proc Natl Acad Sci USA 85:953–957[Abstract/Free Full Text]
248. Rostene WH, Alexander MJ 1997 Neurotensin and neuroendocrine regulation. Front Neuroendocrinol 18:115–173[CrossRef][Medline]
249. Kiss A, Palkovits M, Antoni FA, Eskay RL, Skirboll LR 1987 Neurotensin in the rat median eminence: the possible sources of neurotensin-like fibers and varicosities in the external layer. Brain Res 416:129–135[CrossRef][Medline]
250. McCann SM, Vijayan E 1992 Control of anterior pituitary hormone secretion by neurotensin. Ann NY Acad Sci 668:287–297[CrossRef][Medline]
251. Pan JT, Tian Y, Lookingland KJ, Moore KE 1992 Neurotensin-induced activation of hypothalamic dopaminergic neurons is accompanied by a decrease in pituitary secretion of prolactin and -melanocyte-stimulating hormone. Life Sci 50:2011–2017[CrossRef][Medline]
252. Hentschel K, Cheung S, Moore KE, Lookingland KJ 1998 Pharmacological evidence that neurotensin mediates prolactin-induced activation of tuberoinfundibular dopamine neurons. Neuroendocrinology 68:71–76[CrossRef][Medline]
253. Van de Kar LD, Rittenhouse PA, Li Q, Levy AD 1996 Serotonergic regulation of renin and prolactin secretion. Behav Brain Res 73:203–208[Medline]
254. Vanhatalo S, Soinila S, Kaartinen K, Back N 1995 Colocalization of dopamine and serotonin in the rat pituitary gland and in the nuclei innervating it. Brain Res 669:275–284[CrossRef][Medline]
255. Raap DK, Van de Kar LD 1999 Selective serotonin reuptake inhibitors and neuroendocrine function. Life Sci 65:1217–1235[CrossRef][Medline]
256. Pilotte NS, Porter JC 1981 Dopamine in hypophysial portal plasma and prolactin in systemic plasma of rats treated with 5-hydroxytryptamine. Endocrinology 108:2137–2141[Abstract/Free Full Text]
257. Mathiasen JR, Tomogane H, Voogt JL 1992 Serotonin-induced decrease in hypothalamic tyrosine hydroxylase activity and corresponding increase in prolactin release are abolished at midpregnancy and by transplants of rat choriocarcinoma cells. Endocrinology 131:2527–2532[Abstract/Free Full Text]
258. Balsa JA, Sanchez-Franco F, Pazos F, Lara JI, Lorenzo MJ, Maldonado G, Cacicedo L 1998 Direct action of serotonin on prolactin, growth hormone, corcticotropin and luteinizing hormone release in cocultures of anterior and posterior pituitary lobes: autocrine and/or paracrine action of vasoactive intestinal peptide. Neuroendocrinology 68:326–333[CrossRef][Medline]
259. Lee TY, Pan JT 2001 Involvement of central GABAergic neurons in basal and diurnal changes of tuberoinfundibular dopaminergic neuronal activity and prolactin secretion. Life Sci 68:1965–1975[CrossRef][Medline]
260. Willems E, Knigge U, Jorgensen H, Kjaer A, Warberg J 2000 Effect of blockade of postsynaptic H1 or H2 receptors or activation of presynaptic H3 receptors on catecholamine-induced stimulation of ACTH and prolactin secretion. Eur J Endocrinol 142:637–641[Abstract]
261. Nansel DD, Gudelsky GA, Porter JC 1979 Subcellular localization of dopamine in the anterior pituitary gland of the rat: apparent association of dopamine with prolactin secretory granules. Endocrinology 105:1073–1077[Abstract/Free Full Text]
262. Arita J, Reymond MJ, Porter JC 1984 Evidence for alteration in the processing of dopamine in the anterior pituitary gland of aged rats: receptors and intracellular compartmentalization of dopamine. Endocrinology 114:974–979[Abstract/Free Full Text]
263. Gallardo MG, Bilinski M, Chiocchio SR, Tramezzani JH 1985 Dopamine enters lactotrophs and reaches their secretory granules. J Endocrinol 104:23–28[Abstract/Free Full Text]
264. Ju G, Liu S, Zhang X 1991 Peptidergic innervation of the mammalian anterior pituitary. News Physiol Sci 6:26–28[Abstract/Free Full Text]
265. Bayet MC, Schussler N, Verney C, Peillon F 1994 Tyrosine- hydroxylase immunoreactive fibres in the rat anterior pituitary. Neuroreport 5:1505–1508[Medline]
266. Schussler N, Bayet MC, Frain O, Peillon F, Biguet NF 1992 Evidence of tyrosine hydroxylase mRNA in the anterior and neurointermediate lobes of female rat pituitary. Biochem Biophys Res Commun 189:1716–1724[CrossRef][Medline]
267. Schussler N, Boularand S, Li JY, Peillon F, Mallet J, Biguet NF 1995 Multiple tyrosine hydroxylase transcripts and immunoreactive forms in the rat: differential expression in the anterior pituitary and adrenal gland. J Neurosci Res 42:846–854[CrossRef][Medline]
268. Iturriza FC, Rubio MC, Dumm CLA, Zieher LM 1983 Catecholamine metabolizing enzymes and synthesis of dopamine in normal and grafted pituitary pars distalis. Neuroendocrinology 37:371–377[Medline]
269. Yoshinaga N, Murayama T, Nomura Y 1998 Death by a dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+) and protection by EGF in GH3 cells. Brain Res 794:137–142[CrossRef][Medline]
270. Mitsuma T, Rhue H, Hirooka Y, Kayama M, Wago T, Takagi J, Adachi K, Ping J, Ohtake M, Nogimori T, Sakai J 1998 Distribution of dopamine transporter in the rat: an immunohistochemical study. Endocr Regul 32:71–75[Medline]
271. Inazu M, Takeda H, Ikoshi H, Uchida Y, Kubota N, Kiuchi Y, Oguchi K, Matsumiya T 1999 Regulation of dopamine uptake by basic fibroblast growth factor and epidermal growth factor in cultured rat astrocytes. Neurosci Res 34:235–244[CrossRef][Medline]
272. Autelitano DJ, Snyder L, Sealfon SC, Roberts JL 1989 Dopamine D2-receptor messenger RNA is differentially regulated by dopaminergic agents in rat anterior and neurointermediate pituitary. Mol Cell Endocrinol 67:101–105[CrossRef][Medline]
273. Giros B, Sokoloff P, Martres MP, Riou JF, Emorine LJ, Schwartz JC 1989 Alternative splicing directs the expression of two D2 dopamine receptor isoforms. Nature 342:923–926[CrossRef][Medline]
274. Dal Toso R, Sommer B, Ewert M, Herb A, Pritchett DB, Bach A, Shivers BD, Seeburg PH 1989 The dopamine D2 receptor: two molecular forms generated by alternative splicing. EMBO J 8:4025–4034[Medline]
275. Renner U, Arzberger T, Pagotto U, Leimgruber S, Uhl E, Muller A, Lange M, Weindl A, Stalla GK 1998 Heterogeneous dopamine D2 receptor subtype messenger ribonucleic acid expression in clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 83:1368–1375[Abstract/Free Full Text]
276. McChesney R, Sealfon SC, Tsutsumi M, Dong KW, Roberts JL, Bancroft C 1991 Either isoform of the dopamine D2 receptor can mediate dopaminergic repression of the rat prolactin promoter. Mol Cell Endocrinol 79:R1–R7
277. Senogles SE 2000 The D2 s dopamine receptor stimulates phospholipase D activity: a novel signaling pathway for dopamine. Mol Pharmacol 58:455–462[Abstract/Free Full Text]
278. Guivarc’h D, Vincent J-D, Vernier P 1998 Alternate splicing of the D₂ dopamine receptor messenger ribonucleic acid is modulated by activated sex steroid receptors in the MMQ prolactin cell line. Endocrinology 139:4213–4221[Abstract/Free Full Text]
279. Arnauld E, Arsaut J, Demotes-Mainard J 1991 Differential plasticity of the dopaminergic D2 receptor mRNA isoforms under haloperidol treatment, as evidenced by in situ hybridization in rat anterior pituitary. Neurosci Lett 130:12–16[CrossRef][Medline]
280. Pasqualini C, Bojda F, Kerdelhue B 1986 Direct effect of estradiol on the number of dopamine receptors in the anterior pituitary of ovariectomized rats. Endocrinology 119:2484–2489[Abstract/Free Full Text]
281. Johnston JM, Wood DF, Read S, Johnston DG 1993 Dopamine regulates D2 receptor gene expression in normal but not in tumorous rat pituitary cells. Mol Cell Endocrinol 92:63–68[CrossRef][Medline]
282. Missale C, Castelletti L, Boroni F, Memo M, Spano P 1991 Epidermal growth factor induces the functional expression of dopamine receptors in the GH3 cell line. Endocrinology 128:13–20[Abstract/Free Full Text]
283. Missale C, Boroni F, Losa M, Giovanelli M, Zanellato A, Dal Toso R, Balsari A, Spano P 1993 Nerve growth factor suppresses the transforming phenotype of human prolactinomas. Proc Natl Acad Sci USA 90:7961–7965[Abstract/Free Full Text]
284. Missale C, Losa M, Sigala S, Balsari A, Giovanelli M, Spano PF 1996 Nerve growth factor controls proliferation and progression of human prolactinoma cell lines through an autocrine mechanism. Mol Endocrinol 10:272–285[Abstract/Free Full Text]
285. Missale C, Boroni F, Sigala S, Zanellato A, Dal Toso R, Balsari A, Spano P 1994 Nerve growth factor directs differentiation of the bipotential cell line GH-3 into the mammotroph phenotype. Endocrinology 135:290–298[Abstract]
286. Minowa T, Minowa MT, Mouradian MM 1992 Analysis of the promoter region of the rat D2 dopamine receptor gene. Biochemistry 31:8389–8396[CrossRef][Medline]
287. Minowa T, Minowa MT, Mouradian MM 1994 Negative modulator of the rat D2 dopamine receptor gene. J Biol Chem 269:11656–11662[Abstract/Free Full Text]
288. Valdenaire O, Vernier P, Maus M, Dumas Milne Edwards JB, Mallet J 1994 Transcription of the rat dopamine-D2-receptor gene from two promoters. Eur J Biochem 220:577–584[Medline]
289. Gregerson KA 2001 Mechanism of dopamine action on the lactotrophs. In: Horseman ND, ed. Prolactin. Boston: Kluwer; 45–61
290. Corrette BJ, Bauer CK, Schwarz JR 1995 Electrophysiology of anterior pituitary cells. In: Scherubl H, Hescheler J, eds. The electrophysiology of neuroendocrine cells. London: CRC Press; 101–143
291. Ho M-Y, Kao JPY, Gregerson KA 1996 Dopamine withdrawal elicits prolonged calcium rise to support prolactin rebound release. Endocrinology 137:3513–3521[Abstract]
292. Lledo P-M, Legendre P, Israel J-M, Vincent J-D 1990 Dopamine inhibits two characterized voltage-dependent calcium currents in identified rat lactotroph cells. Endocrinology 127:990–1001[Abstract/Free Full Text]
293. Curtis BM, Catterall WA 1985 Phosphorylation of the calcium antagonist receptor of the voltage-sensitive calcium channel by cAMP-dependent protein kinase. Proc Natl Acad Sci USA 82:2528–2532[Abstract/Free Full Text]
294. Nastainczyk W, Rohrkasten A, Sieber M, Rudolph C, Schachtele C, Marme D, Hofmann F 1987 Phosphorylation of the purified receptor for calcium channel blockers by cAMP kinase and protein kinase C. Eur J Biochem 169:137–142[Medline]
295. Denef C, Manet D, Dewals R 1980 Dopaminergic stimulation of prolactin release. Nature 285:243–246[CrossRef][Medline]
296. Burris TP, Freeman ME 1993 Low concentrations of dopamine increase cytosolic calcium in lactotrophs. Endocrinology 133:63–68[Abstract/Free Full Text]
297. Shin SH 1999 Dopamine agonists both stimulate and inhibit prolactin release in GH4ZR7 cells. Eur J Endocrinol 141:387–395[Abstract]
298. Porter TE, Grandy D, Bunzow J, Wiles CD, Civelli O, Frawley LS 1994 Evidence that stimulatory dopamine receptors may be involved in the regulation of prolactin secretion. Endocrinology 134:1263–1268[Abstract/Free Full Text]
299. Kineman RD, Gettys TW, Frawley LS 1994 Paradoxical effects of dopamine (DA): Gia3 mediates DA inhibition of PRL release while masking its PRL-releasing activity. Endocrinology 135:790–793[Abstract]
300. De La Escalera GM, Weiner RI 1992 Dissociation of dopamine from its receptor as a signal in the pleiotropic hypothalamic regulation of prolactin secretion. Endocr Rev 13:241–255[Abstract/Free Full Text]
301. Enjalbert A, Musset F, Chenard C, Priam M, Kordon C, Heisler S 1988 Dopamine inhibits prolactin secretion stimulated by the calcium channel agonist Bay-K-8644 through a pertussis toxin-sensitive G protein in anterior pituitary cells. Endocrinology 123:406–412[Abstract/Free Full Text]
302. Taussig R, Gilman AG 1995 Mammalian membrane-bound adenylyl cyclases. J Biol Chem 270:1–4[Free Full Text]
303. Diamond SE, Chiono M, Gutierrez-Hartmann A 1999 Reconstitution of the protein kinase A response of the rat prolactin promoter: differential effects of distinct Pit-1 isoforms and functional interaction with Oct-1. Mol Endocrinol 13:228–238[Abstract/Free Full Text]
304. Chuang TT, Caccavelli L, Kordon C, Enjalbert A 1993 Protein kinase C regulation of prolactin gene expression in lactotroph cells: involvement in dopamine inhibition. Endocrinology 132:832–838[Abstract/Free Full Text]
305. Vallar L, Vicentini LM, Meldolesi J 1988 Inhibition of inositol phosphate production is a late, Ca2+-dependent effect of D2 dopaminergic receptor activation in rat lactotroph cells. J Biol Chem 263:10127–10134[Abstract/Free Full Text]
306. Rhodes SJ, diMattia GE, Rosenfeld MG 1994 Transcriptional mechanisms in anterior pituitary cell differentiation. Curr Opin Gen Dev 4:709–717[CrossRef][Medline]
307. Lew AM, Elsholtz HP 1995 A dopamine-responsive domain in the N-terminal sequence of Pit-1. Transcriptional inhibition in endocrine cell types. J Biol Chem 270:7156–7160[Abstract/Free Full Text]
308. Nguyen B, Carbajal ME, Vitale ML 1999 Intracellular mechanisms involved in dopamine-induced actin cytoskeleton organization and maintenance of a round phenotype in cultured rat lactotrope cells. Endocrinology 140:3467–3477[Abstract/Free Full Text]
309. Leong DA, Lau SK, Sinha YN, Kaiser DL, Thorner MO 1985 Enumeration of lactotropes and somatotropes among male and female pituitary cells in culture: evidence in favor of a mammosomatotrope subpopulation in the rat. Endocrinology 116:1371–1378[Abstract/Free Full Text]
310. Johansen PW, Haug E, Gautvik KM 1985 Effects of bromocriptine on hormone production and cell growth in cultured rat pituitary cells. Acta Endocrinol (Copenh) 110:200–206[Abstract/Free Full Text]
311. Phelps CJ, Hymer WC 1988 Effects of bromocriptine on prolactin cellular hypertrophy, proliferation and secretory activity in diethylstilbestrol-induced pituitary tumors. Mol Cell Endocrinol 58: 137–148
312. Borgundvaag B, Kudlow JE, Mueller SG, George SR 1992 Dopamine receptor activation inhibits estrogen-stimulated transforming growth factor- gene expression and growth in anterior pituitary, but not in uterus. Endocrinology 130:3453–3458[Abstract/Free Full Text]
313. Pastorcic M, De A, Boyadjieva N, Vale W, Sarkar DK 1995 Reduction in the expression and action of transforming growth factor ß1 on lactotropes during estrogen-induced tumorigenesis in the anterior pituitary. Cancer Res 55:4892–4898[Abstract/Free Full Text]
314. Arita J, Hashi A, Hoshi K, Mazawa S, Suzuki S 1998 D2 dopamine-receptor-mediated inhibition of proliferation of rat lactotropes in culture is accompanied by changes in cell shape. Neuroendocrinology 68:163–171[CrossRef][Medline]
315. McLaughlin BA, Nelson D, Erecinska M, Chesselet MF 1998 Toxicity of dopamine to striatal neurons in vitro and potentiation of cell death by a mitochondrial inhibitor. J Neurochem 70:2406–2415[Medline]
316. Lahteenmaki P, Marrs RP, Schechter J, Zacharias S, Kletzky OA 1985 Hormonal and morphologic effects of bromocriptine on normal rat pituitary and GH3 tumor cells. Am J Obstet Gynecol 153:349–357[Medline]
317. Zhang Y, Cincotta AH 1997 Inhibitory effects of bromocriptine on vascular smooth muscle cell proliferation. Atherosclerosis 133:37–44[CrossRef][Medline]
318. Kanasaki H, Fukunaga K, Takahashi K, Miyazaki K, Miyamoto E 2000 Involvement of p38 mitogen-activated protein kinase activation in bromocriptine-induced apoptosis in rat pituitary GH3 cells. Biol Reprod 62:1486–1494[Abstract/Free Full Text]
319. Saiardi A, Bozzi Y, Baik J-H, Borrelli E 1997 Antiproliferative role of dopamine: loss of D₂ receptors causes hormonal dysfunction and pituitary hyperplasia. Neuron 19:115–126[CrossRef][Medline]
320. Kelly MA, Rubinstein M, Asa SL, Zheng G, Saez C, Bunzow JR, Allen R, Hnasko RM, Ben-Jonathan N, Grandy DK, Low MJ 1997 Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19:103–113[CrossRef][Medline]
321. Blackwell RE 1992 Hyperprolactinemia: evaluation and management. Reprod Endocrinol 21:105–124
322. Asa SL, Kelly MA, Grandy D, Low MJ 1999 Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. Endocrinology 140:5348–5355[Abstract/Free Full Text]
323. Krown KA, Wang Y-F, Ho TWC, Kelly PA, Walker AM 1992 Prolactin isoform 2 as an autocrine growth factor for GH3 cells. Endocrinology 131:595–602[Abstract/Free Full Text]
324. Hyde JF, Keller BK 1991 Galanin secretion from anterior pituitary cells in vitro is regulated by dopamine, somatostatin, and thyrotropin-releasing hormone. Endocrinology 128:917–922[Abstract/Free Full Text]
325. Ochoa A, Mitchner NA, Paynter C, Ben-Jonathan N 2000 Vascular endothelial growth factor (VEGF) in the rat pituitary: Differential distribution and regulation by estrogen. J Endocinol 165:483–492[Abstract]
326. Lew AM, Yao H, Elsholtz HP 1994 G_i2- and G_o-mediated signaling in the Pit-1-dependent inhibition of the prolactin gene promoter. Control of transcription by dopamine D2 receptors. J Biol Chem 269:12007–1[Abstract/Free Full Text]
327. McCarthy GF, Beaudet A, Tannenbaum GS 1992 Colocalization of somatostatin receptors and growth hormone-releasing factor immunoreactivity in neurons of the rat arcuate nucleus. Neuroendocrinology 56:18–24[Medline]
328. Ormandy CJ, Camus A, Barra J, Damotte D, Lucas B, Buteau H, Edery M, Brousse N, Babinet C, Binart N, Kelly PA 1997 Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev 11:167–178[Abstract/Free Full Text]
329. Horseman ND, Zhao W, Montecino-Rodriguez E, Tanake M, Nakashima K, Engle SJ, Smith F, Markoff E, Dorshkind K 1997 Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J 16:6926–6935[CrossRef][Medline]
330. Davis JA, Linzer DI 1989 Expression of multiple forms of the prolactin receptor in mouse liver. Mol Endocrinol 3:674–680[Abstract/Free Full Text]
331. Ferrara N, Clapp C, Weiner R 1991 The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 129:896–900[Abstract/Free Full Text]
332. Binart N, Helloco C, Ormandy CJ, Barra J, Clement-Lacroix P, Baran N, Kelly PA 2000 Rescue of preimplantatory egg development and embryo implantation in prolactin receptor-deficient mice after progesterone administration. Endocrinology 141:2691–2697[Abstract/Free Full Text]
333. Lucas BK, Ormandy CJ, Bridges RS, Kelly PA 1998 Null mutation of the prolactin receptor gene produces a defect in maternal behavior. Endocrinology 139:4102–4107[Abstract/Free Full Text]
334. Phelps CJ, Horseman ND 2000 Prolactin gene disruption does not compromise differentiation of tuberoinfundibular dopaminergic neurons. Neuroendocrinology 72:2–10[CrossRef][Medline]
335. Steger RW, Chandrashekar V, Zhao W, Bartke A, Horseman ND 1998 Neuroendocrine and reproductive functions in male mice with targeted disruption of the prolactin gene. Endocrinology 139:3691–3695[Abstract/Free Full Text]
336. Bartke A 1999 Role of growth hormone and prolactin in the control of reproduction: what are we learning from transgenic and knock-out animals? Steroids 64:598–604[CrossRef][Medline]
337. Wennbo H, Kindblom J, Isaksson OGP, Tornell J 1997 Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland. Endocrinology 138:4410–4415[Abstract/Free Full Text]
338. Ling C, Hellgren G, Gebre-Medhin M, Dillner K, Wennbo H, Carlsson B, Billig H 2000 Prolactin (PRL) receptor gene expression in mouse adipose tissue: increases during lactation and in PRL-transgenic mice. Endocrinology 141:3564–3572[Abstract/Free Full Text]
338. Wennbo H, Gebre-Medhin M, Gritli-Linde A, Ohlsson C, Isaksson OG, Tornell J 1997 Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest 100:2744–2751[Medline]
339. Phelps CJ, Bartke A 1997 Stimulatory effect of human, but not bovine, growth hormone expression on numbers of tuberoinfundibular dopaminergic neurons in transgenic mice. Endocrinology 138:2849–2855[Abstract/Free Full Text]
340. Couse JF, Korach KS 1999 Estrogen receptor null mice: What have we learned and where will they lead us? Endocr Rev 20:358–417[Abstract/Free Full Text]
341. Scully KM, Gleiberman AS, Lindzey J, Lubahn DB, Korach KS, Rosenfeld MG 1997 Role of estrogen receptor- in the anterior pituitary gland. Mol Endocrinol 11:674–681[Abstract/Free Full Text]
342. Weihua Z, Saji S, Makinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA 2000 Estrogen receptor (ER) ß, a modulator of ER in the uterus. Proc Natl Acad Sci USA 97:5936–5941[Abstract/Free Full Text]
343. Korach KS 2000 Estrogen receptor knock-out mice: molecular and endocrine phenotypes. J Soc Gynecol Investig 7:S16–S17
344. Hyde JF, Engle MG, Maley BE 1991 Colocalization of galanin and prolactin within secretory granules of anterior pituitary cells in estrogen-treated Fischer 344 rats. Endocrinology 129:270–276[Abstract/Free Full Text]
345. Bedecs K, Berthold M, Bartfai T 1995 Galanin–10 years with a neuroendocrine peptide. Int J Biochem Cell Biol 27:337–349[CrossRef][Medline]
346. Wynick D, Small CJ, Bloom SR 1998 Targeted disruption of the murine galanin gene. Anal NY Acad Sci 863:22–47[CrossRef][Medline]
347. Cai A, Hayes JD, Patel N, Hyde JF 1999 Targeted overexpression of galanin in lactotrophs of transgenic mice induces hyperprolactinemia and pituitary hyperplasia. Endocrinology 140: 4955–4964
348. Lindsay RM 1996 Role of neurotrophins and trk receptors in the development and maintenance of sensory neurons: an overview. Philos Trans R Soc Lond B Biol Sci 351:365–373[Medline]
349. Ibanez CF 1994 Structure-function relationships in the neurotrophin family. J Neurobiol 25:1349–1361[CrossRef][Medline]
350. Ray D, Melmed S 1997 Pituitary cytokine and growth factor expression and action. Endocr Rev 18:206–228[Abstract/Free Full Text]
351. Schwartz J 2000 Intercellular communication in the anterior pituitary. Endocr Rev 21:488–513[Abstract/Free Full Text]
352. Lahtinen T, Soinila S, Lakshmanan J 1989 Biological demonstration of nerve growth factor in the rat pituitary gland. Neuroscience 30:165–170[CrossRef][Medline]
353. Missale C, Boroni F, Sigala S, Buriani A, Fabris M, Leon A, Dal Toso R, Spano P 1996 Nerve growth factor in the anterior pituitary: localization in mammotroph cells and cosecretion with prolactin by a dopamine-regulated mechanism. Proc Natl Acad Sci USA 93:4240–4245[Abstract/Free Full Text]
354. Borrelli E, Sawchenko PE, Evans RM 1992 Pituitary hyperplasia induced by ectopic expression of nerve growth factor. Proc Nat Acad Sci USA 89:2764–2768[Abstract/Free Full Text]
355. Missale C, Spano P 1998 Nerve growth factor in pituitary development and pituitary tumors. Front Neuroendocrinol 19:128–150[CrossRef][Medline]
356. Proesmans M, Van Bael A, Andries M, Denef C 1997 Mitogenic effects of nerve growth factor on different cell types in reaggregate cell cultures of immature rat pituitary. Mol Cell Endocrinol 134:119–127[CrossRef][Medline]
357. Asa SL, Kovacs K, Laszlo FA, Domokos I, Ezrin C 1986 Human fetal adenohypophysis: Histologic and immunocytochemical analysis. Neuroendocrinology 43:308–316[CrossRef][Medline]
358. Mulchahey JJ, DiBlasio AM, Martin MC, Blumenfeld Z, Jaffe RB 1987 Hormone production and peptide regulation of the human fetal pituitary gland. Endocr Rev 8:406–425[Abstract/Free Full Text]
359. Gluckman PD, Grumbach MM, Kaplan SL 1981 The neuroendocrine regulation and function of growth hormone and prolactin in the mammalian fetus. Endocr Rev 2:363–395[Abstract/Free Full Text]
360. Frawley LS, Neill JD 1983 Neuroendocrine regulation of prolactin secretion in primates. In: Bhatnagar AS, ed. The anterior pituitary gland. New York: Raven Press; 253–268
361. McNeilly AS, Gilmore D, Dobbie G, Chard T 1977 Prolactin releasing activity in the early human foetal hypothalamus. J Endocrinol 73:533–534[Abstract/Free Full Text]
362. Roti E, Robuschi G, Alboni A, d’Amato L, Montermini M, Gardini E, Salvi M, Borciani E, Dall’Aglio E, Bisi S 1986 Human foetal prolactin but not thyrotropin secretion is decreased by bromocriptine. Acta Endocrinol (Copenh) 112:35–42[Abstract/Free Full Text]
363. Van den BG, de Zegher F, Lauwers P 1994 Dopamine suppresses pituitary function in infants and children. Crit Care Med 22:1747–1753[Medline]
364. Kubota T, Nagae M, Yaoi Y, Kumasaka T, Saito M 1986 Prolactin-releasing system in maternal, fetal, and amniotic compartments during labor. Obstet Gynecol 68:80–85[Medline]
365. Banerjee SK, Sarkar DK, Weston AP, De A, Campbell DR 1997 Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis. Carcinogenesis 18:1155–1161[Abstract/Free Full Text]
366. Rigg LA, Yen SS 1977 Multiphasic prolactin secretion during parturition in human subjects. Am J Obstet Gynecol 128:215–218[Medline]
367. Fernandes PA, Boroditsky RS, Roberts GK, Wodzicki AM, McCoshen JA 1999 The acute release of maternal prolactin by instrumental cervical dilatation simulates the second stage of labor. J Soc Gynecol Investig 6:22–26[Medline]
368. Handwerger S, Brar A 2001 Human uteroplacental lactogens: Physiology and molecular biology. In: Horseman ND, ed. Prolactin. Boston: Kluwer; 169–188
369. diMattia GE, Gellersen B, Duckworth ML, Friesen HG 1990 Human prolactin gene expression. J Biol Chem 265:16412–16421[Abstract/Free Full Text]
370. Golander A, Barrett J, Hurley T, Barry S, Handwerger S 1979 Failure of bromocriptine, dopamine, and thyrotropin-releasing hormone to affect prolactin secretion by human decidual tissue in vitro. J Clin Endocrinol Metab 49:787–789[Abstract/Free Full Text]
371. Brar AK, Frank GR, Kessler CA, Cedars MI, Handwerger S 1997 Progesterone-dependent decidualization of the human endometrium is mediated by cAMP. Endocrine 6:301–307[Medline]
372. Ben-Jonathan N, Munsick RA 1980 Dopamine and prolactin in human pregnancy. J Clin Endocrinol Metab 51:1019–1025[Abstract/Free Full Text]
373. Sarandakou A, Kassanos D, Phocas I, Kontoravdis A, Chryssicopoulos A, Zourlas PA 1992 Amniotic fluid hormone profiles during normal and abnormal pregnancy. Clin Exp Obst Gyn 7: 180–188
374. Hennart P, Delogne-Desnoeck J, Vis H, Robyn C 1981 Serum levels of prolactin and milk production in women during a lactation period of thirty months. Clin Endocrinol (Oxf) 14:349–353[Medline]
375. McNeilly AS, Robinson IC, Houston MJ, Howie PW 1983 Release of oxytocin and prolactin in response to suckling. Br Med J (Clin Res Ed) 286:257–259
376. Stern JM, Konner M, Herman TN, Reichlin S 1986 Nursing behaviour, prolactin and postpartum amenorrhoea during prolonged lactation in American and !Kung mothers. Clin Endocrinol (Oxf) 25:247–258[Medline]
377. Fujimoto VY, Clifton DK, Cohen NL, Soules MR 1990 Variability of serum prolactin and progesterone levels in normal women: the relevance of single hormone measurements in the clinical setting. Obstet Gynecol 76:71–78[Medline]
378. Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB 1997 Tissue distribution of estrogen receptors (ER-) and ß (ER-ß) mRNA in the midgestational human fetus. J Clin Endocrinol Metab 82:3509–3512[Abstract/Free Full Text]
378. Lamberts SW, Verleun T, Hofland L, Oosterom R 1986 Differences in the interaction between dopamine and estradiol on prolactin release by cultured normal and tumorous human pituitary cells. J Clin Endocrinol Metab 63:1342–1347[Abstract/Free Full Text]
379. Henry JP 1992 Biological basis of the stress response. Integr Physiol Behav Sci 27:66–83[Medline]
380. Carlson HE 1989 Prolactin stimulation by protein is mediated by amino acids in humans. J Clin Endocrinol Metab 69:7–14[Abstract/Free Full Text]
381. Weitzman ED 1982 Chronobiology of man. Sleep, temperature and neuroendocrine rhythms. Hum Neurobiol 1:173–183[Medline]
382. Carlson HE 1995 Drugs and pituitary function. In: Melmed S, ed. The pituitary. Cambridge, MA: Blackwell Science; 645–662
383. Zhang Y, Dawson VL, Dawson TM 2000 Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol Dis 7:240–250[CrossRef][Medline]
384. Przedborski S, Jackson-Lewis V 1998 Mechanisms of MPTP toxicity. Mov Disord 13(Suppl 1):35–38
385. Agnoli A, Baldassarre M, Ruggieri S, Falaschi P, Urso RD, Rocco A 1981 Prolactin response as an index of dopaminergic receptor function in Parkinson’s disease. Correlation with clinical findings and therapeutic response. J Neural Transm 51:123–134[CrossRef]
386. Franceschi M, Camerlingo M, Perego L, Bottacchi E, Truci G, Mamoli A 1988 Tuberoinfundibular dopaminergic function in Parkinson’s disease. Eur Neurol 28:117–119[CrossRef][Medline]
387. Andreasen NC 2000 Schizophrenia: the fundamental questions. Brain Res Brain Res Rev 31:106–112[CrossRef][Medline]
388. Hyman SE 2000 The NIMH perspective: next steps in schizophrenia research. Biol Psychiatry 47:1–7[CrossRef][Medline]
389. Terenius L 2000 Schizophrenia: pathophysiological mechanisms–a synthesis. Brain Res Brain Res Rev 31:401–404[CrossRef][Medline]
390. Carlsson A, Waters N, Carlsson ML 1999 Neurotransmitter interactions in schizophrenia–therapeutic implications. Biol Psychiatry 46:1388–1395[CrossRef][Medline]
391. Lindstrom LH 1996 Clinical and biological markers for outcome in schizophrenia: a review of a longitudinal follow-up study in Uppsala schizophrenia research project. Neuropsychopharmacology 14:23S–26S
392. Zakzanis KK, Hansen KT 1998 Dopamine D2 densities and the schizophrenic brain. Schizophr Res 32:201–206[CrossRef][Medline]
393. Tallman JF 2000 Development of novel antipsychotic drugs. Brain Res Brain Res Rev 31:385–390[CrossRef][Medline]
394. Dickson RA, Glazer WM 1999 Neuroleptic-induced hyperprolactinemia. Schizophr Res 35 Suppl:S75–S86
395. Kuruvilla A, Peedicayil J, Srikrishna G, Kuruvilla K, Kanagasabapathy AS 1992 A study of serum prolactin levels in schizophrenia: comparison of males and females. Clin Exp Pharmacol Physiol 19:603–606[Medline]
396. Peabody CA, Warner MD, Griffin M, Boutros NN, Worsley IG, Friesen HG 1992 Prolactin bioassay in schizophrenia before and after neuroleptics. Psychiatry Res 41:249–255[CrossRef][Medline]
397. Walker AM, Peabody CA, Ho TW, Warner MD 1992 50 kD prolactin binding protein in schizophrenics on neuroleptic medication. J Psychiatry Neurosci 17:61–67[Medline]
398. Raap DK, Van de Kar LD 1999 Selective serotonin reuptake inhibitors and neuroendocrine function. Life Sci 65:1217–1235
399. Juruena MF, Pires ML, Calil HM 1997 Moclobemide effects on prolactin plasma levels in healthy individuals: the hormonal increase induced by a single dose is maintained during a 4-week period of drug intake. Int Clin Psychopharmacol 12:317–321[Medline]
400. Delitala G, Grossman A, Besser M 1983 Differential effects of opiate peptides and alkaloids on anterior pituitary hormone secretion. Neuroendocrinology 37:275–279[Medline]
401. Kreek MJ, Schluger J, Borg L, Gunduz M, Ho A 1999 Dynorphin A1–13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions. J Pharmacol Exp Ther 288:260–269[Abstract/Free Full Text]
402. Ur E, Wright DM, Bouloux PM, Grossman A 1997 The effects of spiradoline (U-62066E), a -opioid receptor agonist, on neuroendocrine function in man. Br J Pharmacol 120:781–784[CrossRef][Medline]
403. Brown CK, Khanderia U 1990 Use of metoclopramide, domperidone, and cisapride in the management of diabetic gastroparesis. Clin Pharm 9:357–365[Medline]
404. Kelley SR, Kamal TJ, Molitch ME 1996 Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia. Am J Physiol 270:E96–100
405. Baldini M, Cornelli U, Molinari M, Cantalamessa L 1988 Effect of methyldopa on prolactin serum concentration. Comparison between normal and sustained-release formulations. Eur J Clin Pharmacol 34:513–515[CrossRef][Medline]
406. Vance ML, Thorner MO 1987 Prolactinomas. Endocrinol Metab Clin North Am 16:731–753[Medline]
407. Molitch ME 2001 Prolactinomas. In: Horseman ND, ed. Prolactin. Boston: Kluwer; 81–100
408. Asa SL, Ezzat S 1998 The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19:798–827[Abstract/Free Full Text]
409. Spada SA, Vallar L, Faglia G 1994 Cellular alterations in pituitary tumors. Eur J Endocrinol 130:43–52[Abstract/Free Full Text]
410. Elias KA, Weiner RI 1984 Direct arterial vascularization of estrogen-induced prolactin-secreting anterior pituitary tumors. Proc Nat Acad Sci USA 81:4549–4553[Abstract/Free Full Text]
411. Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S 1990 Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 71:1427–1433[Abstract/Free Full Text]
412. Alexander JM, Biller BM, Bikkal H, Zervas NT, Arnold A, Klibanski A 1990 Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest 86:336–340
413. Evans CO, Brown MR, Parks JS, Oyesiku NM 2000 Screening for MEN1 tumor suppressor gene mutations in sporadic pituitary tumors. J Endocrinol Invest 23:304–309[Medline]
414. Pei L, Melmed S 1997 Isolation and characterization of a pituitary tumor-transforming gene. Mol Endocrinol 11:433–441[Abstract/Free Full Text]
415. Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, Melmed S 1999 Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 84:761–767[Abstract/Free Full Text]
416. Heaney AP, Horwitz GA, Wang Z, Singson R, Melmed S 1999 Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nature Med 5:1317–1321[CrossRef][Medline]
417. Colao A, Lombardi G 1998 Growth-hormone and prolactin excess. Lancet 352:1455–1461[CrossRef][Medline]
418. Stevenaert A, Beckers A, Vandalem JL, Hennen G 1986 Early normalization of luteinizing hormone pulsatility after successful transsphenoidal surgery in women with microprolactinomas. J Clin Endocrinol Metab 62:1044–1047[Abstract/Free Full Text]
419. Milenkovic L, D’Angelo G, Kelly PA, Weiner RI 1994 Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors. Proc Natl Acad Sci USA 91:1244–1247[Abstract/Free Full Text]
420. Ginsburg KA 1992 Luteal phase defect. Etiology, diagnosis, and management. Endocrinol Metab Clin North Am 21:85–104[Medline]
421. Sanfilippo JS 1999 Implications of not treating hyperprolactinemia. J Reprod Med 44:1111–1115[Medline]
422. Pinzone JJ, Katznelson L, Danila DC, Pauler DK, Miller CS, Klibanski A 2000 Primary medical therapy of micro- and macroprolactinomas in men. J Clin Endocrinol Metab 85:3053–3057[Abstract/Free Full Text]
423. Leonard MP, Nickel CJ, Morales A 1989 Hyperprolactinemia and impotence: why, when and how to investigate. J Urol 142:992–994[Medline]
424. Maccagnan P, Macedo CLD, Kayath MJ, Ogueira RG, Bucham J 1995 Conservative management of pituitary apoplexy: a prospective study. J Clin Endocrinol Metab 80:2190–2197[Abstract]
425. Peter M, De Tribolet N 1995 Visual outcome after transsphenoidal surgery for pituitary adenomas. Br J Neurosurg 9:151–157[CrossRef][Medline]
426. Pliam M, Cohen M, Cheng L, Spaenle M, Bronstein MH, Atkins TW 1995 Pituitary adenomas complicating cardiac surgery: summary and review of 11 cases. J Card Surg 10:125–132[Medline]
427. Ho KY, Thorner MO 1988 Therapeutic applications of bromocriptine in endocrine and neurological diseases. Drugs 36:67–82
428. Molitch ME 1999 Medical treatment of prolactinomas. Endocrinol Metab Clin North Am 28:143–169, vii[CrossRef][Medline]
429. Caccavelli L, Feron F, Morange I, Rouer E, Benarous R, Dewailly D, Jaquet P, Kordon C, Enjalbert A 1994 Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology 60:314–322[Medline]
430. Pontikides N, Krassas GE, Nikopoulou E, Kaltsas T 2000 Cabergoline as a first-line treatment in newly diagnosed macroprolactinomas. Pituitary 2:277–281[CrossRef][Medline]

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				B. Liu and L. A. Arbogast Phosphorylation State of Tyrosine Hydroxylase in the Stalk-Median Eminence Is Decreased by Progesterone in Cycling Female Rats Endocrinology, April 1, 2008; 149(4): 1462 - 1469. [Abstract] [Full Text] [PDF]

				C. E. Khodr, S. M. Clark, D. L. Hurley, and C. J. Phelps Long-Term, Homologous Prolactin, Administered through Ectopic Pituitary Grafts, Induces Hypothalamic Dopamine Neuron Differentiation in Adult Snell Dwarf Mice Endocrinology, April 1, 2008; 149(4): 2010 - 2018. [Abstract] [Full Text] [PDF]

				M. J. Millan, F. Loiseau, A. Dekeyne, A. Gobert, G. Flik, T. I. Cremers, J.-M. Rivet, D. Sicard, R. Billiras, and M. Brocco S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: III. Actions in Models of Therapeutic Activity and Induction of Side Effects J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1212 - 1226. [Abstract] [Full Text] [PDF]

				R. I. Holt Medical causes and consequences of hyperprolactinaemia. A context for psychiatrists J Psychopharmacol, March 1, 2008; 22(2_suppl): 28 - 37. [Abstract] [PDF]

				N. Ben-Jonathan, C. R. LaPensee, and E. W. LaPensee What Can We Learn from Rodents about Prolactin in Humans? Endocr. Rev., February 1, 2008; 29(1): 1 - 41. [Abstract] [Full Text] [PDF]

				A. Gruszka, S.-G. Ren, J. Dong, M. D. Culler, and S. Melmed Regulation of Growth Hormone and Prolactin Gene Expression and Secretion by Chimeric Somatostatin-Dopamine Molecules Endocrinology, December 1, 2007; 148(12): 6107 - 6114. [Abstract] [Full Text] [PDF]

				M. Ishida, T. Mitsui, K. Yamakawa, N. Sugiyama, W. Takahashi, H. Shimura, T. Endo, T. Kobayashi, and J. Arita Involvement of cAMP response element-binding protein in the regulation of cell proliferation and the prolactin promoter of lactotrophs in primary culture Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1529 - E1537. [Abstract] [Full Text] [PDF]

				K. C. Horner, Y. Cazals, R. Guieu, M. Lenoir, and N. Sauze Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1224 - E1232. [Abstract] [Full Text] [PDF]

				D. T. McKee, M. O. Poletini, R. Bertram, and M. E. Freeman Oxytocin Action at the Lactotroph Is Required for Prolactin Surges in Cervically Stimulated Ovariectomized Rats Endocrinology, October 1, 2007; 148(10): 4649 - 4657. [Abstract] [Full Text] [PDF]

				G. Tomei, A. Capozzella, M. Ciarrocca, P. Fiore, M. Valeria Rosati, M. Fiaschetti, T. Casale, V. Anzelmo, F. Tomei, and C. Monti Plasma dopamine in workers exposed to urban stressor Toxicology and Industrial Health, August 1, 2007; 23(7): 421 - 427. [Abstract] [PDF]

				A. Jaubert, G. Drutel, T. Leste-Lasserre, F. Ichas, and L. Bresson-Bepoldin Tyrosine Hydroxylase and Dopamine Transporter Expression in Lactotrophs from Postlactating Rats: Involvement in Dopamine-Induced Apoptosis Endocrinology, June 1, 2007; 148(6): 2698 - 2707. [Abstract] [Full Text] [PDF]

				S. R Valdez, A. B Penissi, R. P Deis, and G. A Jahn Hormonal profile and reproductive performance in lactation deficient (OFA hr/hr) and normal (Sprague-Dawley) female rats Reproduction, April 1, 2007; 133(4): 827 - 840. [Abstract] [Full Text] [PDF]

				M. C. Zatelli, M. R. Ambrosio, M. Bondanelli, and E. C d. Uberti Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds Eur. J. Endocrinol., April 1, 2007; 156(suppl_1): S29 - S35. [Abstract] [Full Text] [PDF]

				B. W. Dunlop and C. B. Nemeroff The Role of Dopamine in the Pathophysiology of Depression Arch Gen Psychiatry, March 1, 2007; 64(3): 327 - 337. [Full Text] [PDF]

				E. R. Samuels, R. H. Hou, R. W. Langley, E. Szabadi, and C. M. Bradshaw Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers J Psychopharmacol, November 1, 2006; 20(6): 756 - 770. [Abstract] [PDF]

				M. Chesterfield, J. Janik, E. Murphree, C. Lynn, E. Schmidt, and P. Callahan Orphanin FQ/Nociceptin Is a Physiological Regulator of Prolactin Secretion in Female Rats Endocrinology, November 1, 2006; 147(11): 5087 - 5093. [Abstract] [Full Text] [PDF]

				G. M. Anderson, P. Beijer, A. S. Bang, M. A. Fenwick, S. J. Bunn, and D. R. Grattan Suppression of Prolactin-Induced Signal Transducer and Activator of Transcription 5b Signaling and Induction of Suppressors of Cytokine Signaling Messenger Ribonucleic Acid in the Hypothalamic Arcuate Nucleus of the Rat during Late Pregnancy and Lactation Endocrinology, October 1, 2006; 147(10): 4996 - 5005. [Abstract] [Full Text] [PDF]