Dopaminergic Neuronal Systems in the Hypothalamus

Kenneth E. Moore and Keith J. Lookingland

INTRODUCTION

The roles of mesotelencephalic dopaminergic (DA) neuronal systems in regulating basic neurological functions including integrative control of muscle movement and affective behaviors have been established, and dysfunctions of these systems have long been associated with neurological disease states including Parkinson’s disease and schizophrenia.  Therapeutic strategies for treatment of these disorders typically utilize drugs that act directly at specific DA receptors (or indirectly via increased DA release) to activate receptors in the case of Parkinson's disease, or block receptors in the case of schizophrenia.  Since DA receptors participate in the regulation of other neurological functions, these strategies may produce unwanted side effects, some of which could mimic or disrupt non-targeted  DA neuronal systems, including hypothalamic DA neurons.

In a previous review published in 1987 (75) it was pointed out that there are differences in the characteristics of neurons that comprise the various anatomically differentiated DA neuronal systems in the mammalian brain.  Indeed, evidence available at that time revealed that neurochemical properties and responses to pharmacological and endocrinological manipulations of the major ascending mesotelencephalic DA neurons are often quite different from those DA neurons that originate in the diencephalon (i.e., those neurons identified as the A₁₁, A₁₂, A₁₃ and A₁₄ cell groups by the alphanumeric system of Dahlström and Fuxe (12).  This chapter provides an updated review of these hypothalamic DA neurons.

Anatomical Overview

Details of the anatomy of DA perikarya in the rat diencephalon are provided by Björklund et al. (9) the location of their perikarya are depicted schematically in Fig. 1 .  There are comparable numbers of DA perikarya in the rat diencephalon (A₁₁, A₁₂, A₁₃ and A₁₄; 112) as in the substantia nigra (A₈ and A₉; 25, 26) or ventral tegmental area (A₁₀; 25, 26), which are generally considered to be the major loci of DA neurons in the brain.  The most familiar hypothalamic DA neurons are those that comprise the tuberoinfundibular (TI) DA system; perikarya of these neurons (A₁₂), which are located in the mediobasal hypothalamic arcuate nucleus and adjacent periventricular nucleus, project to the external layer of the median eminence (Fig. 2).  Although TIDA neurons have been studied more extensively than other DA neurons in the diencephalon they actually represent a minority of these DA neurons (83).  The majority of diencephalic DA neurons are located in dorsal regions of the hypothalamus and ventral thalamus, and the regions adjacent to the third ventricle.  A small number of relatively large DA perikarya (A₁₁) are located in the posterior regions of the dorsal hypothalamus and the periventricular gray of the central thalamus; axons from these neurons project to the spinal cord.  Due to the paucity of information regarding the function of these diencephalospinal DA neurons they will not be discussed in this chapter.

DA perikarya identified as the A₁₃ cell group are clustered in the rostral regions of the medial zona incerta (MZI) and comprise the incertohypothalamic (IH) DA system.  Perikarya of these densely packed DA neurons have extensive dendritic processes oriented in the ventral plane which extend into the dorsomedial nucleus of the hypothalamus (102).  Early reports using histochemical fluorescence techniques suggested that efferents of IHDA neurons project diffusely into the surrounding anterior, dorsomedial and posterior regions of the hypothalamus (9).  The results of more recent anatomical (104) and neurochemical studies (19) suggest, however, that IHDA neurons project much more extensively than originally believed, innervating a variety of anatomically discrete brain regions including the central nucleus of the amygdala, horizontal diagonal band of Broca and hypothalamic paraventricular nucleus.  The relative contribution of IHDA neurons to these regions varies; i.e. DA terminals in the paraventricular nucleus originate exclusively from IHDA neurons in the MZI, whereas IHDA neurons provide only a portion of the DA innervation of  the amygdala and horizontal diagonal band of Broca (11).  The majority of DA input to these latter two regions originates from midbrain mesolimbic DA neurons.

DA neurons projecting to the posterior pituitary were reported initially to originate from rostral A₁₂ cells in the arcuate and periventricular nuclei; accordingly, they were referred to as tuberohypophysial DA neurons.  A more recent study (28) revealed that DA neurons projecting to the intermediate lobe of the pituitary originate from a subpopulation of A₁₄ DA cells in the periventricular nucleus (Fig. 3).  In this review DA neurons projecting to the intermediate lobe of the pituitary will be identified as the periventricular-hypophysial dopaminergic (PHDA) neurons, although in the majority of earlier references these neurons are referred to as tuberohypophysial DA neurons.  The remaining A₁₄ periventricular (PeV) DA neurons are believed to project laterally into adjacent regions (e.g. medial preoptic area, anterior hypothalamic area).  Additional details of the distribution of TIDA, IHDA, PHDA and PeVDA neurons can be found in the following sections dealing with each of these neuronal systems.

Estimation of the Activity of Hypothalamic DA Neurons

Only a few investigators have attempted to directly measure the activity (or impulse flow) of hypothalamic DA neurons.  For example, Sanghera (87) and Eaton and Moss (16) recorded electrical activity from neurons in the MZI in response to a variety of pharmacological manipulations using both in situ and in vitro slice preparations.  Several laboratories have recorded electrical activity in slices of the mediobasal hypothalamus, particularly from neurons in the arcuate nucleus (51), but only a few studies determined unequivocally that recordings were made from DA neurons (59, 109). 

Alternatively, investigators have employed a variety of neurochemical techniques to estimate neurotransmitter release from hypothalamic DA neurons.  The basis of these biochemical techniques is that the release of DA is coupled to the rates of synthesis and metabolism of DA in terminals and dendrites of DA neurons.  Procedures that increase or decrease neurotransmitter release from DA neurons generally do not alter steady state concentrations of DA but produce corresponding increases or decreases, respectively, in rates of synthesis, turnover and metabolism of this amine.  The utility of various neurochemical procedures for estimating activity of hypothalamic DA neurons has been discussed previously (75), and only reviewed briefly and updated in this section.

A number of investigators have employed in vitro techniques to characterize neurochemical properties of TIDA and PHDA neurons, but as this chapter will focus on the responses of hypothalamic DA neuronal systems to physiological and pharmacological manipulations, discussions will be limited to results obtained using in vivo techniques.  Early in vivo attempts to estimate the activity of central catecholaminergic neurons involved studies that employed α-methyltyrosine, an inhibitor of tyrosine hydroxylase (TH).  Following administration of α-methyltyrosine the concentrations of catecholamines are reduced in an exponential manner at a rate that is proportional to the activity of the neurons that contain these amines.  The advantage of this technique is that it permits concurrent estimation of DA and norepinephrine (NE) turnover in the same hypothalamic brain region.  There are, however, several disadvantages to this procedure: 1) measurement of catecholamines must be made in groups of animals killed immediately before and at least two different times after α-methyltyrosine administration so as to assure that an exponential rate of decline has occured, 2) rapid measurements cannot be made which prohibits its use for short term experimental manipulations, and 3) by virtue of its ability to block synthesis α-methyltyrosine reduces catecholamine release which compromises neuronal function.  This is a problem when studying TIDA neurons in that blockade of DA synthesis in TIDA neurons reduces DA release into the hypophysial portal blood thereby removing DA inhibition of prolactin secretion from the anterior pituitary.  The increase in circulating prolactin feeds back to increase activity of TIDA neurons.

The rate of catecholamine synthesis is regulated at the step catalyzed by TH so estimates of catecholaminergic activity can be obtained from measurements of the activity of this enzyme.  This can be accomplished in vivo by administering 3-hydroxybenzylhydrazine (NSD 1015), an inhibitor of aromatic amino acid decarboxylase.  The concentration of 3,4-dihydroxyphenylalanine (DOPA) in brain tissue is essentially zero because once it is synthesized from tyrosine it is immediately decarboxylated to DA.  Following the administration of NSD 1015, DOPA accumulates in catecholaminergic nerve terminals at a rate that is proportional to the activity of these neurons.  The advantages of this procedure over the α-methyltyrosine technique are that fewer measurements are needed (DOPA concentrations are so low that 'zero-time' values are unnecessary), and they can be made over a shorter time frame (i.e. as soon as 15 min after i.v. NSD 1015).  As with α-methyltyrosine, NSD 1015 disrupts catecholamine synthesis and thereby alters the properties of the catecholaminergic neurons (e.g., NSD 1015, like α-methyltyrosine, increases plasma levels of prolactin).  Finally, DOPA accumulates in both DA and noradrenergic (NE) neurons after the administration of NSD 1015.  This has little consequence when DOPA accumulation is measured in terminals of TIDA and PHDA neurons in the median eminence or intermediate lobe of the pituitary since the concentrations and turnover of DA greatly exceed those of NE.  In most hypothalamic regions, however, the concentrations of NE are greater than DA so this procedure cannot be employed to estimate IHDA or PeVDA neuronal activity.

In brain regions containing a preponderance of DA over NE nerve terminals the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a major metabolite of DA, reflect the activity of DA neurons.  It has been shown empirically that increases and decreases in TIDA and PHDA neuronal activities are accompanied by concurrent increases and decreases in DOPAC concentrations in the median eminence and intermediate lobe of the pituitary, respectively (53, 56).  In contrast to techniques that require administration of α-methyltyrosine or NSD 1015, no drug pretreatments are required prior to the measurement of DOPAC concentrations; accordingly, measurements can be made within minutes after initiating a manipulation.

In the following discussions alterations in hypothalamic DA neuronal activity (i.e. increases or decreases in neurotransmitter release) were estimated using one or more of the neurochemical methods described above.

TUBEROINFUNDIBULAR DOPAMINERGIC NEURONS

Anatomy

Perikarya of TIDA (A₁₂) neurons are located in the arcuate nucleus and adjacent periventricular region of the rat mediobasal hypothalamus (12).  Within the arcuate nucleus, two populations of TH-containing neurons have been identified on the basis of their size and location in either the dorsomedial or ventrolateral regions of this nucleus (21).  In the dorsomedial arcuate nucleus and adjacent periventricular nucleus, relatively small DA perikarya have dendrites oriented in the dorsoventral plane (102) and axons which project ventrally to terminate in the external layer of the median eminence (9).  High affinity DA uptake by TIDA neurons is modest presumably due to less DA transporter protein and lower affinity of the transporter for DA as compared with other central DA neurons with “classical” post synaptic target receptors (75, 82).  DA released from terminals of TIDA neurons in the median eminence does not enter a synapse but diffuses through fenestrated capillaries and is transported in the hypophysial portal blood to the anterior pituitary where it activates D₂ receptors on lactotrophs and tonically inhibits the secretion of prolactin from these cells.  TH-containing perikarya in the ventrolateral arcuate nucleus are larger in size (21) with dendrites oriented in the mediolateral plane (93) and axons that terminate in the lateral portion of the median eminence (9).  These neurons lack L-aromatic amino acid decarboxylase (21, 70), and they do not express DA transporter protein mRNA as do the DA-containing neurons in the dorsomedial portion of the arcuate nucleus (72).  "DOPAergic" neurons have also been identified in the ventrolateral arcuate nuleus of the human brain, and although their functional significance is unknown, it has been suggested that DOPA released from these neurons may be decarboxylated to DA in the hypothalamic-pituitary vasculature (70). 

TIDA neurons in the dorsomedial arcuate nucleus also synthesize a number of neuromodulators/neurotransmitters reported to have either inhibitory (GABA, galanin, enkephalin) or stimulatory (neurotensin) effects on DA release from these neurons (21).  It has been postulated that these co-localized neurotransmitters may be selectively synthesized and released under different physiological conditions thereby modulating TIDA neuronal regulation of prolactin secretion, and the responsiveness of these neurons to hormonal and neuronal feedback (71).

Neurochemistry

Each of the neurochemical techniques described above in the Introduction has been used effectively to estimate TIDA neuronal activity and have provided consistent results.  The terminal region of these neurons, the median eminence, is well defined and relatively easy to dissect, and the concentration and rate of turnover of DA are much higher than those of NE so there is no difficulty in relating changes in DOPA accumulation or DOPAC concentrations to TIDA activity (36, 56).  The activity of these neurons has also been estimated from measurements of the amount of DA released into hypophysial portal blood, but since this technique involves use of anesthetized animals following radical surgery, there has been little use of this technique in recent years.  Neurochemical estimates of TIDA neuronal activity have been correlated with reciprocal changes in circulating levels of prolactin.  One should be cognizant, however, that while the primary control of prolactin secretion is exerted by the inhibitory actions of TIDA neurons, the secretion of prolactin under some circumstances is influenced by prolactin-releasing factors.

Regulation of Activity

The properties and responses of TIDA neurons differ in many respects from those of other DA neuronal systems in the mammalian brain.  Some of these differences were discussed in previous reviews (75); additions to and updates of these differences are described below.

Sexual differences

There are marked differences in the activities of TIDA neurons of male and female rats.  Although there is no sexual difference in the density of TIDA nerve terminals (as reflected in the concentration of DA in the median eminence), the rates of turnover, synthesis and metabolism of DA in this region, and the concentration of DA in hypophysial portal blood is 2-3 times higher in female than in male rats.  TIDA neuronal activity is increased in the male and decreased in the female after castration, and these effects are reversed by replacement with testosterone (99) or with estrogen (101), respectively.  The ability of estrogen to increase TIDA neuronal activity in ovariectomized rats is secondary to the ability of this hormone to increase circulating levels of prolactin.  The higher set point of TIDA neuronal activity in females may be physiologically relevant for regulation of episodic hormone secretion since prolactin surges which occur during the afternoon of proestrous, pregnancy, and lactation are all associated with suppression of TIDA neuronal activity and loss of DA inhibition of prolactin secretion.  These topics have been reviewed elsewhere (75), and will not be discussed here.

There are also major sexual differences in the responses of TIDA neurons to a variety of pharmacological and physiological manipulations.  TIDA neurons in females are more responsive to the stimulating actions of prolactin, the inhibitory effects of stress (57), and administration of kappa opioid agonists (66) and the N-methyl-D-asparate receptor antagonist MK801 (105).  On the other hand, activation of TIDA neurons after administration of bombesin (100) and a kappa opioid antagonist (66) is more pronounced in the male.  Additional details of the responses of TIDA neurons in male and female rats are provided in the following sections which describe the actions of individual drugs.

Effects of prolactin

Under most physiological situations the activity of TIDA neurons is regulated, to a large extent, by circulating levels of prolactin; other DA neurons are unresponsive to this hormone.  TIDA neuronal activity is reduced during periods of hypoprolactinemia, such as that caused by hypophysectomy, or the administration of DA agonists or prolactin antibody.  The reduction of TIDA neuronal activity is more pronounced in the female; indeed, following several hours of low circulating levels of prolactin the activity of these neurons in the female rat is equivalent to that seen in a male with normal prolactin levels.  On the other hand, TIDA neuronal activity is increased during periods of hyperprolactinemia; for example, following implantation of prolactin-secreting tumors, administration of DA antagonists or estrogen, and the central or systemic administration of prolactin.  TIDA neurons in the female rat are more sensitive and responsive to prolactin than they are in the male. 

The mechanism by which prolactin activates TIDA neurons has not been elucidated, but the effects of this hormone are delayed and dependent upon protein synthesis (46) suggesting that de novo synthesis and release of a neuropeptide neurotransmitter may mediate the stimulatory actions of prolactin on these neurons.   A number of peptidergic receptors have been identified which could mediate the delayed stimulatory effects of prolactin on TIDA neurons; among these neurotensin, bombesin/gastrin-releasing peptide, and delta opioid receptors are reasonable candidates (66, 77).  Indeed, the ability of a neurotensin antagonist to block prolactin-induced increases in median eminence DOPAC concentrations (38) is consistent with a role for neurotensin receptors in mediating the stimulatory effects of prolactin on TIDA neurons.

Putative afferent neurotransmitters

To date, the majority of studies on TIDA neurons has focused on responses of these neurons to changes in the hormonal milieu (e.g., prolactin, gonadal steroids; 75).  It is apparent, however, that TIDA neurons are also acutely responsive to afferent neuronal influences as evidenced by the rapid responses of these neurons in female rats to stressful manipulations and suckling, both of which promptly inhibit TIDA neuronal activity and thereby increase plasma concentrations of prolactin (75).  The neuronal circuits responsible for stress or suckling-induced inhibition of TIDA neurons have not been well-defined, but since the responses can be attenuated by antagonists of recognized neurotransmitters (e.g., 5-hydroxytryptamine [5HT], acetylcholine), it is reasonable to assume that neurons utilizing these transmitters are located somewhere in neuronal circuits activated by stressful or suckling stimuli.  A number of attempts have been made to employ pharmacolog­ical techniques to uncover roles played by putative aminergic and peptidergic neurotransmitters in regulating TIDA neuronal activity.  The following sections review some of the effects of putative neurotransmitters, and their agonists and antagonists, on TIDA neuronal activity and secretion of prolactin.

Drugs which act as selective agonists or antagonists at mu, kappa or delta opioid receptors produce characteristic patterns of responses of different DA neurons.  Morphine and a variety of mu opioid agonists increase the activity of the major mesotelencephalic DA neurons terminating in the striatum and limbic forebrain regions (75), but inhibit TIDA neurons.  Inhibition of TIDA neurons is responsible, at least in part, for increased circulating levels of prolactin produced by mu opioid agonists.  The inhibitory action of mu opioids on TIDA neurons appears due to their ability to hyperpolarize these neurons by increasing potassium conductance (59).

Endogenous mu opioids may play a role in the physiological regulation of TIDA neurons.  For example, in lactating, but not in male or estrous female rats, TIDA neurons synthesize enkephalin (73).  Enkephalin released from TIDA neurons during lactation may act on mu opioid “autoreceptors” to inhibit DA release, and thereby maintain high circulating levels of prolactin and milk production.

Drugs that act at kappa opioid receptors also influence the activity of DA neurons, but unlike mu opioid agonists (which depending on the neuronal system can increase or decrease the activity of DA neurons), kappa agonists exert only inhibitory actions.  The degree of inhibition is generally dependent upon the level of activity of the DA neurons at the time the kappa agonist is administered.  For example, the kappa agonist U50,488 exerts only minimal inhibitory actions on nigrostriatal, mesolimbic or TIDA neurons unless these neurons are activated (64).  U50,488 also reduces the high level of activity of TIDA neurons in female rats, but is without effect in males unless the latter animals are injected with prolactin or are orchidectomized in order to activate their TIDA neurons (66).  On the other hand, the selective kappa opioid receptor antagonist norbinaltorphimine increases TIDA neuronal activity in male but not in female rats suggesting that in males TIDA neurons are tonically inhibited by the endogenous kappa opioid dynorphin.  Consistent with this suggestion icv administration of dynorphin antibodies to male rats increases the activity of TIDA neurons (67).

There have been few studies on the responses of hypothalamic DA neurons to drugs that act at delta opioid receptors, but these drugs exert a pattern of effects that is different from that of drugs acting on mu or kappa opioid receptors (68).  In male rats icv injection of [D-Pen², D-Pen⁵]enkephalin, an delta opioid receptor agonist, has no effect on nigrostriatal DA neurons, but increases the activity of TIDA and mesolimbic DA neurons terminating in nucleus accumbens.  These effects are blocked by naltrindole, a selective delta-opioid receptor antagonist, but this antagonist has no effect per se on DA neuronal systems.

Several neuroactive peptides stimulate TIDA neurons; the most potent of these is bombesin.  Intracerebroventricular injection of this peptide into male rats at doses as low as 1 ng causes a marked but relative short-lasting increase in TIDA neuronal activity and a concomitant decrease in plasma concentrations of prolactin (65).  Even at a higher doses this peptide is without effect on activities of nigrostriatal or mesolimbic DA neurons.  These stimulatory effects of bombesin are mimicked by equimolar concentrations of gastrin-releasing peptide (GRP), a bombesin-like peptide found in mammalian brain.  The activation of TIDA neurons by bombesin and GRP are blocked by a bombesin antagonist (MDL 101,562), but blockade of bombesin/GRP receptors per se is without effect, suggesting that under basal conditions these hypothalamic DA neurons are not under tonic excitatory control of a bombesin-like peptide (69).  The stimulatory effect of bombesin on TIDA neurons does not involve prolactin, but since the response is pronounced in ovariectomized but not in gonadally-intact rats it would appear that the stimulatory actions of bombesin in the female are reduced by estrogen (100).

Two other peptides, αMSH and neurotensin, have been reported to activate TIDA neurons.  Central administration of αMSH increases TIDA neuronal activity, and thereby reduces circulating concentrations of prolactin (54).  In contrast, αMSH did not alter the activity of nigrostriatal or mesolimbic DA neurons.  Neurotensin is a peptide neurotransmitter located in neurons in the mediobasal hypothalamus (40).  Following icv administration of this peptide TIDA neurons are activated (32), and neurotensin-induced activation of TIDA neurons is related temporally with a decrease in plasma concentrations of prolactin (77).  Blockade of neurotensin receptors prevents prolactin-induced increases in median eminence DOPAC concentrations suggesting that endogenous neurotensin may play a role in prolactin feedback activation of TIDA neurons (38).

Galanin is a peptide which inhibits the activity of TIDA neurons in both female and male rats (27).  The effects of this peptide on TIDA neurons is activity-dependent in that galanin only inhibits the activity of TIDA neurons under stimulated conditions, but has no effect on the basal activity of these neurons in either gender.  This may represent an autoregulatory feedback mechanism by which galanin co-localized and released from TIDA neurons regulates DA release.

A number of amino acid-derived neurotransmitters presumably released from hypothalamic interneurons are reported to have either stimulatory (e.g. excitatory amino acids) or inhibitory (e.g. GABA) effects on the activity of TIDA neurons.  Glutamate acting at N-methyl-D-aspartate (NMDA) receptors tonically stimulates the basal activity of TIDA neurons in female, but not male rats (105).  This sexual difference in NMDA receptor-mediated regulation of TIDA neuronal activity is likely due to estrogen-induced stimulation of glutamate release by a prolactin-independent mechanism (105).  In both genders, endogenous excitatory amino acids acting at non-NMDA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors tonically inhibit the basal activity of TIDA neurons (107) by a mechanism involving GABA_A receptors (106).  Activation of GABA_B receptors also decreases the basal activity of TIDA neurons, but these neurons are not tonically inhibited by endogenous GABA acting at GABA_B receptors (31).

Psychoactive Drugs

Antipsychotics

Acute administration of "classical" antipsychotics with D₂ receptor antagonistic properties (e.g., haloperidol) activates DA neurons that comprise the mesotelencephalic systems, but has no direct action on TIDA neurons.  On the other hand, TIDA neurons are activated indirectly several hours after administra­tion of haloperidol and other D₂ antagonists as a result of their ability to increase circulating concentrations of prolactin (75).  By contrast, some atypical neuroleptics, exemplified by clozapine, increase acutely TIDA neuronal activity (33).  Although it has been proposed that the ability of clozapine to activate TIDA neurons involves interactions with D₁ DA receptors and/or neurotensin, the mechanism by which clozapine increases the activity of these neurons remains to be elucidated.  This action of clozapine may, however, be responsible for the drug's brief elevation of plasma prolactin levels compared to the long duration of its other effects.  That is, the clozapine increased release of DA from TIDA neurons may counteract the antagonistic actions it has on release of prolactin from lactotrophs in the anterior pituitary.

DA agonists

By activating autoreceptors and/or DA receptor-mediated neuronal feedback loops, non-selective DA agonists (e.g., apomorphine, bromocriptine) reduce the activities of those DA neurons that comprise the mesotelencephalic systems, but TIDA neurons are unresponsive to the acute administration of these drugs (75).  Utilization of second generation agonists which differentiate between the D₁-like and D₂-like subtype families of DA receptors has revealed that TIDA neurons are also regulated by a DA receptor-mediated mechanism which acts independently of prolactin (18).  Indeed, acute administration of DA agonists with preferential affinity for the D₂ family of DA receptors (i.e. quinpirole and quinelorane) stimulates TIDA neurons (8, 18).  This stimulatory action of D₂ agonists appears to occur via an afferent neuronal mechanism involving, in part, disinhibition of tonically active dynorphinergic interneurons (14).  The inability of D₂ receptor antagonists to alter the activity of TIDA neurons per se suggests that there is little intrinsic endogenous DA agonism of the D₂ receptor under basal conditions (18).  Conversely, acute administration of D₁ agonists (e.g., SKF 38393, CY 208-243) inhibits both “basal” (15) and "activated" TIDA neurons (7).  The opposing actions of stimulatory D₂ and inhibitory D₁ receptors could account for the net lack of effect of mixed D₁/D₂ agonists on TIDA neurons.

Regulation of Gene Expression

Over the last several years significant progress has been made regarding activity-dependent regulation of  gene expression in TIDA neurons, especially with regard to the synthesis of catecholamine biosynthetic enzymes.  Of particular interest is the role of immediate early genes in this process. Indeed, the relative number of TIDA neuronal perikarya in the arcuate nucleus expressing Fos and related antigens (FRA) including FOS, FRA1, FRA2 and FOSB (92) have collectively been correlated with physiological and experimentally-induced changes in long-term gene expression in these neurons (39, 49).  Alterations in FRA expression precede activity-dependent changes in expression of mRNA for TH in TIDA neurons (39, 110), suggesting a role for these transcription factors in the regulation of this rate-limiting enzyme in DA biosynthesis.  

Details of  immediate early gene regulation of TH gene expression in central catecholaminergic neurons have been reviewed recently (48), and will only be briefly summarized here.  Stimulation of FRA expression is generally believed to involve ligand-mediated activation of membrane receptors located on neuronal perikarya and/or dendrites which causes second messenger-mediated Fos-related gene transcription, and synthesis of FRA mRNAs and proteins (41).  In TH neurons, FRA proteins are translocated to the nucleus where they form heterodimers with constititively expressed Jun-related transcription factors that bind to the AP-1 promoter site on the TH gene and facilitate transcription of TH mRNA (44).  Thus, the presence of FRA proteins in nuclei of TH-containing neurons represent a useful neurochemical marker of the responsiveness of discrete populations of TIDA neurons. 

There are sexual differences in immediate early gene expression in TIDA neurons; i.e., the number of TIDA neurons expressing FRA is 2-3 times higher in females than males in all but the most caudal region of the dorsomedial arcuate nucleus (16).  This suggests that comparable sexual differences in expression of TH mRNA (3) and the neurochemical activity of TIDA neurons in the median eminence (75) may be due, in part, to greater numbers of active TIDA neurons in females.  Sexual differences in FRA expression in TIDA neurons are gonadal steroid-dependent; ovariectomy decreases, while orchidectomy increases the number of TIDA neurons expressing FRA in the dorsomedial arcuate nucleus, and these gonadectomy-induced effects are reversed by estrogen and testosterone, respectively (16).  Gonadal steroids also regulate the expression of TH mRNA in TIDA neurons in both sexes.  Estrogen suppresses expression of TH mRNA in ovariectomized females, and this effect is reversed by progesterone (4).  In males, orchidectomy increases the mass (or amount) of TH in the median eminence, but has no effect on expression of TH mRNA in TIDA neurons (1).  These results suggest that testosterone regulates the translation of TH mRNA, but not the transcription of the TH gene.  Since many of these changes are disconcordant with the effects of estrogen and testosterone on FRA expression in TIDA neurons (16), it is unlikely that immediate early genes mediate gonadal steroid-induced changes in TH expression.

Several lines of evidence indicate that prolactin-induced alterations in the activity of  TIDA neuron are accompanied by changes in long-term gene expression that result in the ability of these neurons to respond to chronic stimulation (74).  Indeed, prolactin induces expression of mRNA for TH in TIDA neurons in both females (2) and males (90), and “tonic” prolactin stimulation is necessary for sustaining the higher basal TH mRNA expression in TIDA neurons in females (2).  Prolactin also increases the numbers of TIDA neurons expressing FRA in the arcuate nucleus of female and male rats (37).  Hyperprolactinemia increases expression of nur/77 mRNA in chemically-unidentified neurons in regions of the arcuate nucleus containing TIDA neurons (85), but the role of these (as well as FRA) transcription factors in mediating prolactin-induced activation of TH mRNA in TIDA neurons is currently unknown.

PERIVENTRICULAR-HYPOPHYSIAL DOPAMINERGIC NEURONS

Anatomy

DA axons terminating in the posterior pituitary were postulated initially to constitute a distinct tuberohypophysial DA neuronal system originating from A₁₂ perikarya located in the most rostral extent of the arcuate nucleus (9).  A more recent study (28) revealed that DA neurons terminating in the intermediate lobe of the posterior pituitary originate from a sub-population of A₁₄ DA neurons located in the periventricular nucleus dorsal to the retrochiasmatic area of the anterior hypothalamus.  These PHDA neurons have dendrites oriented in the dorsoventral plane (91) and axons that project ventrally through the internal layer of the median eminence and pituitary stalk to terminate in close proximity to intermediate lobe melanotrophs.  DA released from PHDA neurons tonically inhibits the secretion of the pro-opiomelanocortin-derived peptide hormones α-MSH (28) and ß-endorphin from melanotrophs in the intermediate lobe.  In addition, DA neurons terminating in the intermediate lobe have been implicated in the regulation of prolactin secretion (5).

PHDA neurons also contain substances known to have both stimulatory (neurotensin; 43) and inhibitory (GABA; 103) effects on the release of DA in the intermediate lobe.  In addition, terminals of PHDA neurons take up and store 5HT (86), but the role of this amine and other co-localized neurotransmitters in the regulation of PHDA neurons and melanotroph hormone secretion is unknown.

Neurochemistry

Concentrations and rates of turnover of DA greatly exceed those of NE in the intermediate lobe of the pituitary, the terminal region of PHDA neurons, so increases and decreases in PHDA neuronal activity are reflected in concurrent changes in rates of DA turnover and DOPA accumulation (36), and in concentrations of DOPAC in this region (53).  Changes in neurochemical estimations of the activity of these neurons are reflected in changes in their function.  That is, increases and decreases of PHDA neuronal activity are associated with decreases and increases, respectively, in circulating concentrations of αMSH (52).

Regulation of Neuronal Activity

PHDA neurons terminating in the intermediate lobe of the pituitary, unlike the anatomically-related TIDA neurons, do not exhibit pronounced sexual differences, and are unresponsive to changes in circulating levels of gonadal steroids (34).  On the other hand, PHDA neurons resemble the major ascending mestelencephalic DA neurons in that they are regulated by DA receptor-mediated mechanisms.  Acute administration of DA agonists and antagonists cause prompt decreases and increases, respectively, of PHDA neuronal activity (75).

Putative afferent neurotransmitters

Agonists and antagonists of mu (75)  or delta (68) opioid receptors do not alter PHDA neuronal activity.  On the other hand, agonists and antagonists of kappa opioid receptors decrease and increase, respectively, the activity of PHDA neurons and cause reciprocal changes in circulating concentrations of αMSH (62, 63).  The ability of dynorphin antibodies to mimic the stimulatory effects of kappa opioid antagonists on PHDA neurons suggests that these neurons are inhibited tonically by an endogenous dynorphin-containing neuronal system (67).  Other peptides have stimulatory actions on PHDA neurons; i.c.v. administration of bombesin, GRP (65) and neurotensin (77) increase PHDA neuronal activity and cause concomittant decreases in concentration of αMSH in plasma.

Neither increasing activity at histaminergic receptors by i.c.v. administration of histamine nor facilitating release of endogenous histamine influences basal PHDA activity; neither do drugs that inhibit histamine synthesis or block histaminergic receptors (22).  Thus, while histaminergic neuronal systems do not influence basal activity of PHDA neurons, they do play a role in stress-induced inhibition of these neurons (see below).  Similarly, disruption of 5HT tranmission processes fails to alter basal PHDA neuronal activity, but pharmacological activation of 5HT₂ receptors does reduce PHDA neuronal activity and increase αMSH secretion (29).  Furthermore, 5HT neurons are involved in stress-induced inhibition of PHDA neurons (30).

GABA, a dominant inhibitory neurotransmitter in the hypothalamus, is co-localized with DA in neurons innervating the posterior pituitary, and GABA_A and GABA_B receptors are widely distributed in the hypothalamus.  The activity of PHDA neurons is unaltered by pharmacological manipulations of GABA_A receptors, but the GABA_B receptor agonist baclofen reduces PHDA neuronal activity and increases circulating concentrations of αMSH (31).  Selective GABA_B antagonists block these effects of baclofen but have no effect on PHDA neurons per se.  This suggests that under basal conditions GABA neurons are quiescent so that GABA_A and GABA_B receptors are unoccupied and therefore unresponsive to the administration of GABA receptor antagonists.  GABA neurons, however, are involved in the stress-induced inhibition of PHDA neurons (see below).

Stress

While stressful manipulations activate mesolimbic and mesocortical DA neurons they inhibit PHDA neurons and consequently increase secretion of αMSH from the intermediate lobe of the pituitary (58).  Results of pharmacological studies suggest that neurons that transmit information by histamine, 5HT and GABA all play a role in the response of PHDA neurons to stress.

Histaminergic neurons are activated during stress and are involved in the stress-induced inhibition of PHDA neurons; drugs that inhibit histamine synthesis or block H₁ receptors attenuate the reduction of PHDA neuronal activity during stress (23).  5HT neurons also appear to be involved with stress-induced inhibition of PHDA neurons since this response is blocked or attenuated in rats pretreated with 5,7-dihydroxytryptamine to destroy 5HT neurons, with 8-hydroxy-2-(di-n-propylamino)-tetralin to inhibit 5HT neuronal activity, and with 5HT₂ receptor antagonists (29).  Since these pretreatments do not alter basal activity of PHDA neurons it would appear that during non-stressful conditions 5HT neurons are quiescent, but become activated by stressful manipulations.  Since activation of 5HT₂ receptors depolarizes and excites postsynaptic membranes it is unlikely that 5HT neurons inhibit PHDA neurons directly, but during stress act indirectly by activating inhibitory GABA interneurons.  Administration of 2-hydroxysaclofen, a GABA_B antagonist, blocks the inhibition of PHDA neurons and the secretion of αMSH resulting from both the administration of a 5HT₂ agonist and restraint stress (31).

In summary, stressful manipulations activate a chain of neuronal events that are translated into a hormonal response, the release of αMSH from melanotrophs in the intermediate lobe of the pituitary.  This response is the result of two concurrent events: the release from the adrenal medulla of epinephrine which, in turn, releases αMSH by activating ß₂ receptors on melanotrophs, and the removal of inhibitory tone on the melanotroph exerted by PHDA neurons.  Stress-induced inhibition of these neurons appears to be mediated by histaminergic, 5HTergic and GABAergic neurons, the latter two may be arranged in series.  Thus, it appears that PHDA neurons receive a convergence of inhibitory inputs which are important for removing the tonic inhibition of melanotroph secretion during stress.

INCERTOHYPOTHALAMIC DOPAMINERGIC NEURONS

Anatomy

IHDA neurons located in the most rostral portion of the MZI were originally described as the A₁₃ TH containing cell group by Dählström and Fuxe (12).  Perikarya of these densely packed DA neurons have extensive dendritic processes oriented in the ventral plane which extend into the dorsomedial nucleus of the hypothalamus (102).  Early reports using glyoxylic acid histochemical fluorescence techniques suggested that efferents of IHDA neurons project diffusely into the surrounding anterior, dorsomedial and posterior regions of the hypothalamus (9).  The results of later neuroanatomical (104) and neurochemical studies (19) revealed, however, that IHDA neurons project to a variety of anatomically discrete brain regions including the central nucleus of the amygdala, horizontal diagonal band of Broca, and hypothalamic paraventricular nucleus.  The results of recent tract tracing studies demonstrated that the relative contribution of IHDA neurons to these regions varies; i.e. DA terminals in the paraventricular nucleus originate exclusively from IHDA neurons in the MZI, whereas IHDA neurons provide only a portion of the DA innervation of  the amygdala and horizontal diagonal band (11). 

While little information is available regarding the function of IHDA neurons, the distribution of their axonal projections to divergent brain regions suggests that these neurons may function in the integration of autonomic and neuroendocrine responses to specific sensory stimuli.  Indeed, IHDA neurons are located in the most rostral extent of the zona incerta, a diencephalic region involved in processing afferent “sensory” information and integrating efferent “motor” responses (60).  This region receives input from a variety of brain regions involved in sensory processing including the thalamus, hypothalamus, and brain stem reticular formation, and has somatotopically arranged output to all levels of the neuroaxis (84), including the limbic system and hypothalamus (11, 104).  

Neurochemistry

There are two major considerations that should be made when using neurochemical techniques to estimate IHDA neuronal activity.  The first of these is that IHDA neurons project to regions that are also innervated by mesolimbic DA neurons, and accordingly, changes in DA neurochemistry within these regions cannot be attributed exclusively to changes in IHDA neuronal activity.  Since a "pure" IHDA projection region has only been recently identified, investigators have had to rely on neurochemical evaluation of changes in the MZI, which contains soma, dendrites and possibly terminals of IHDA neurons, and the dorsomedial nucleus (DMN) which is reported to contain dendrites and some terminals of IHDA neurons.

A second issue associated with biochemical estimation of DA neuronal activity in the MZI and DMN is that these regions are densely innervated by NE neurons.  Using the tedious α-methyltyrosine technique DA and NE turnover rates have been quantified (75), but DA turnover rates are not useful for determining rapid and/or short-lasting changes in IHDA neuronal activity.  Following NSD 1015 administration DOPA accumulates in both DA and NE neurons within the MZI and DMN so this technique is not useful for estimating IHDA neuronal activity unless NE innervation to these regions has been eliminated.

With some precautions, changes in concentrations of DOPAC and DA in the MZI and DMN can be used to estimate changes in IHDA neuronal activity (97).  DA is a precursor of NE, and as such is present in low concentrations in NE neurons.  When impulse flow in NE neurons increases, TH is activated and the synthesis of DA within NE neurons increases.  Because of limitations imposed by transport of DA into synaptic vesicles and/or the activity of dopamine-ß-hydroxylase, which is located within these vesicles, the concentration of DA within NE neurons increases, and some of the amine is metabolized to DOPAC.  Thus, a concurrent increase in both DOPAC and DA concentrations within a region without a significant change in the DOPAC/DA ratio is usually indicative of an increase in the activity of NE neurons in this region.  If this is the case, the increase in DA and DOPAC will be accompanied by an increase in the concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) a major metabolite of NE.  An increase in DOPAC without a change in DA concentrations (i.e. increase in DOPAC/DA ratio) usually signifies an increase in DA neuronal activity within a region.  In order to substantiate this conclusion it is advisable to determine that concentrations of MHPG do not change and to measure DOPAC/DA ratios in brains in which NE neurons have been destroyed by intracerebral injections of 6-hydroxydopamine (97).

Regulation of Neuronal Activity

IHDA neurons are regulated by DA receptor-mediated mechanisms (75, 97) and in this respect resemble neurons comprising the major ascending mesotelencephalic DA systems.  DA receptor agonists such as apomorphine decrease, whereas DA receptor antagonists such as haloperidol increase the activity of IHDA neurons (75, 97).  In addition, local application of DA inhibits the firing rate of neurons in the MZI possibly by activating autoreceptors on A₁₃ DA perikarya or dendrites (16, 87).  These effects are likely mediated by D₃ (or possibly a subtype of D₂) DA receptors since IHDA neurons are responsive to the mixed D₂/D₃ antagonist raclopride, but not the selective D₂ antagonist remoxipride (17).   

IHDA neurons are activated following acute administration of morphine by a mechanism involving mu opioid receptors (75, 97).  Activation of kappa opioid receptors has no effect on the activity of IHDA neurons (97).  The stimulatory effects of mu opioid receptor activation on IHDA neurons are not dependent upon the presence of 5HT neurons since neurotoxin-induced disruption of 5HT innervation to the hypothalamus does not alter the abililty of morphine to stimulate the activity of IHDA neurons (97).  In this respect, IHDA neurons resemble extrahypothalamic mesotelencephalic DA neurons rather than hypothalamic TIDA neurons.

Another difference between IHDA and TIDA neurons is that IHDA neurons are not responsive to experimentally-induced changes in circulating levels of gonadal steroids or prolactin.  There is no sexual difference in the basal activity of IHDA neurons, and neither castration nor steroid hormone treatment alters the activity of IHDA neurons (35) or TH gene expression in the MZI of either gender (76, 90).  Furthermore, IHDA neurons in the MZI are not responsive to chronic elevations in prolactin concentrations (2, 75, 90) suggesting that these neurons are not involved in the regulation of basal prolactin secretion and do not mediate the effects of hyperprolactinemia on reproductive function.

Although IHDA neurons are unresponsive to hormonal feedback regulation they have been reported to stimulate the preovulatory surge of luteinizing hormone and ovulation (61, 88).  Direct injection of DA or its agonists into the MZI increases luteinizing hormone secretion and causes ovulation by a mechanism involving D₁ receptors (45, 61).  Conversely, lesions of the MZI block the proestrous surge of luteinizing hormone (88) and disrupts estrous cyclicity (61).  The role of efferent projections of IHDA to the horizontal diagonal band of Broca, a region containing gonadotropin releasing hormone perikarya, in regulating preovulatory surges of luteinizing hormone remains to be elucidated.

Elucidation of the function of IHDA neurons has been hampered by the paucity of information on the anatomical location of their axonal projections, but the recent identification of the hypothalamic paraventricular nucleus as a brain region which receives its DA innervation from the MZI suggests a role for IHDA neurons in the regulation of neurosecretory neurons located in this region.  Indeed, pharmacological activation of D₁ and D₂ DA receptors stimulates gene expression in corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (20) suggesting that IHDA neurons participate in neuronal regulation of the hypothalamic-pituitary-adrenal axis.  That central CRH administration increases the metabolism of DA in the paraventricular nucleus (78) suggests that CRH neurons may, in turn, regulate the activity of IHDA neurons projecting to this region. 

PERIVENTRICULAR DOPAMINERGIC NEURONS

Anatomy

Perikarya of A₁₄ PeVDA neurons are distributed in the periventricular nucleus throughout the entire rostrocaudal extent of the third ventricle (102).  Dendrites of these neurons are oriented in the dorsoventral plane and overlap extensively with dendrites from adjacent DA neurons.  PeVDA perikarya are also distributed laterally along the ventral surface of the brain near the supraoptic and suprachiasmatic nuclei (102).  In the rostroventral region of the periventricular nucleus, the distribution of PeVDA neurons is sexually dimorphic in that the number of TH immunoreactive cells and fibers is 2 to 3-fold higher in females than in males (93).  Although little information is available regarding the efferent projections of PeVDA neurons, fibers of these neurons in the rostral periventricular nucleus extend laterally into the adjacent medial preoptic nucleus and anterior hypothalamic area (9).

A number of neuropeptides including neurotensin (43), cholecystokinin, and vasoactive intestine polypeptide (91) are co-localized with DA in the periventricular nucleus, but little information is available regarding the effects of these neurotransmitters on the activity or function of PeVDA neurons.

Neurochemistry

Comments on neurochemical estimation of the activity of IHDA neurons (see above) are also pertinent for PeVDA neurons.  Thus, unless activated NE neurons contribute significantly to tissue concentrations of DOPAC and DA, changes in concentrations of DOPAC and DA in the medial preoptic nucleus and anterior hypothalamic area can be used to estimate changes in PeVDA neuronal activity (97).

Regulation of Neuronal Activity

PeVDA neurons are regulated by DA receptor-mediated mechanisms and in this respect resemble IHDA neurons in the MZI (75).  Acute administration of DA receptor antagonists and agonists increase and decrease, respectively, the activity of DA neurons in the periventricular nucleus and adjacent medial preoptic nucleus and anterior hypothalamic area.  Furthermore, inhibition of neuronal activity following administration of gamma-hydroxybutyrolactone results in an apomorphine-reversible increase in DA concentrations in these regions suggesting that PeVDA neurons are regulated, at least in part, by DA autoreceptors located on dendrites, perikarya and/or axon terminals of these neurons (75). 

PeVDA neurons in the rostral periventricular nucleus and medial preoptic nucleus are activated following acute administration of morphine by a mechanism involving mu opioid receptors (75).  No information is available regarding the effects of kappa or delta opioid receptor activation or blockade on the activity of these neurons. 

In contrast to IHDA neurons, PeVDA neurons in the rostral hypothalamus are responsive to experimentally-induced changes in circulating levels of gonadal steroids and prolactin.  There is a sexual difference in the basal activity of PeVDA neurons projecting to the rostral, periventricular and medial preoptic nuclei with the activity in females being 20-30% higher than males (35).  This sexual difference in the activity of PeVDA neurons in the medial preoptic nucleus could be due, in part, to the inhibitory effects of testosterone in males (94), and/or the stimulatory effects of estrogen in females (75).  Testosterone treatment of orchidectomized males has also been reported to have a stimulatory effect on the activity of PeVDA neurons in the medial preoptic area (35).  Experimental manipulations which produce elevations in circulating prolactin decrease the activity of DA neurons in the medial preoptic area of gonadally-intact males (75), and counteract the inhibitory effects of testosterone on these neurons in orchidectomized males (47).

Although the function of PeVDA neurons is currently unknown, compelling evidence suggests that those neurons terminating in the medial preoptic area are important in regulating male sexual behavior.  Indeed, neurotoxin-induced lesions of DA neurons in the medial preoptic nucleus (6) or direct injection of a DA antagonist into this region (80) decreases male copulatory behavior by a mechanism involving D₂ DA receptor regulation of reflexive and motivational factors, rather than locomotion (111).  This is supported by the observation that DA neuronal activity is increased in the medial preoptic area in males during copulation (42).  In females, DA neurons in the medial preoptic area have been implicated in the regulation estrogen-induced sexual receptivity (112) and in the desensitization of the negative feedback effect of estrogen on luteinizing hormone secretion that occurs during puberty (13).

HYPOTHALAMIC DOPAMINERGIC NEURONS IN THE HUMAN

Information on hypothalamic DA neurons provided above has been obtained primarily from studies conducted in the rat.  There have been relatively few studies on DA neurons in the human brain and the majority of these, as in the rat, have focused on those DA neurons that comprise the nigrostriatal, mesolimbic and mesocortical systems.  Functional studies in humans have revealed that drugs that disrupt DA synthesis or block D₂ DA receptors increase circulating concentrations of prolactin.  This suggests that, as in the rat, the secretion of prolactin is tonically inhibited by DA released from neurons terminating near the primary capillary loops of the hypophysial portal system.

Spencer et al. (95) were the first to map TH-immunoreactive neurons in the male adult human hypothalamus; they noted positive staining cells in the paraventricular, supraoptic, periventricular and arcuate nuclei, and in the dorsal lateral hypothalamus (the latter 3 regions correspond to A₁₄, A₁₂ and A₁₃ regions in the rat, respectively).  Since TH staining neurons in the human hypothalamus are not immunoreactive to dopamine β-hydroxylase antiserum it is assumed they are DA (24).  Using improved immunohistochemical procedures Li et al. (50) and Panaytacoupoulou et al. (79) demonstrated that in the hypothalamus of developing human brain the majority of TH-containing neurons were located in the paraventricular and supraoptic nuclei.  Up to 40% of the magnocellular neurons within these two nuclei contained TH and in many of these neurons this enzyme was colocalized with either vasopressin or oxytocin.  This contrasts to the mouse, rat and rabbit where only a small number of magnocellular neurons in the paraventricular and supraoptic nuclei contain TH (102).  It is interesting, however, that dehydration and hyperosmotic stimuli in the rat increase TH mRNA in magnocellular neurons (113), and this may be the reason for the increased concentration and rate of synthesis of dopamine in terminal regions of these neurons in the posterior pituitary of rats subjected to dehydration or salt loading (see PHDA; 75)

Patients suffering from Parkinson’s disease do not exhibit elevated plasma levels of prolactin suggesting that TIDA neurons remain functional in these patients.  Furthermore, postmortem analyses of parkinsonian brains revealed that, in contrast to the marked loss of dopaminergic neurons in the substantia nigra, there was no loss of TH immunoreactive neurons in the supraoptic, paraventricular, periventricular or arcuate nuclei (87).  It appears, therefore, that hypothalamic dopaminergic neurons do not degenerate in Parkinson’s disease but the reason for their resistance to degeneration does not appear to be the presence of calbindin-D28K because this calcium binding protein that protects neurons from degenerating is colocalized with only a small number of hypothalamic dopaminergic neurons (89).

There is no evidence to support the existence in humans of a DA neuronal system comparable to PHDA neurons in the rat.  A distinct intermediate lobe is present in human fetal and neonatal pituitaries, but the size of this lobe diminishes with age so that in the adult there is no well-defined intermediate lobe.  Although melanotrophs are dispersed throughout the human anterior pituitary it is not known if these cells are innervated by DA neurons or if they respond to the administration of DA agonists and antagonists.  As noted above, little is known about the functions of A₁₃ and rostral A₁₄ DA cell bodies in the rat, and there have been no studies on comparable neurons in the human brain.

SUMMARY AND CONCLUSIONS

A review of hypothalamic DA neurons published in the last volume of Psychopharmacology: The Third Generation of Progress (75) focused primarily on TIDA neurons that tonically inhibit the secretion of prolactin from the anterior pituitary.  It was noted that many properties of these DA neurons are distinctly different from those of the major ascending nigrostriatal and mesolimbic DA neuronal systems.  Although the importance of the hormonal regulation of TIDA neurons was emphasized it was also recognized that these neurons respond acutely to sensory stimuli, but the chemical characteristics of afferent neurons that influence TIDA neurons was largely unknown at that time.  Since 1987 the characteristic responses of TIDA neurons to putative neurotransmitters, and to compounds that mimic the actions of these transmitters have been documented and reviewed here.

New information has also been included regarding activity-related regulation of gene expression in TIDA neurons which results in synthesis of enzymes important for the maintenance of DA synthesis and the ability of these neurons to respond to chronic stimulation.

Over the past few years much has been learned about the hypothalamic DA neurons that innervate the intermediate lobe of the pituitary.  These PHDA neurons, unlike TIDA neurons, are not responsive to changes in hormonal milieu, but are inhibited by stress and are activated or inhibited by a variety of compounds that interfere with or mimic the actions of aminergic or peptidergic neurotransmitters.

Studies on the mechanisms by which TIDA and PHDA neurons are regulated have been assisted greatly by knowledge of the anatomical distribution and functions of these neurons.  Until recently, this has not been the case with IHDA or PeVDA neurons.  The finding that IHDA neurons have discrete projection sites in the horizontal band and hypothalamic paraventicular nucleus should lead to the elucidation of the role these neurons play in regulating neurosecretory neurons located in these regions. The endocrinological consequences of psychoactive drugs that mimic, facilitate or block DA neurotransmission of TIDA and PHDA neurons are well recognized.  The challenge now is to characterize further the functions of the IHDA and PeVDA neurons.  Only then will it be possible to evaluate potential therapeutic or adverse effects of pharmacological manipulations that modify these two, as yet poorly understood, hypothalamic DA systems.

ACKNOWLEDGEMENTS

The authors' studies cited in this review were supported by NIH grants NS15911 and MH42802.

published 2000