1548 FREEMAN,KANYICSKA,LERANT,AND NAGY Volume 80 ical data indicated a tonic inhibito n hasal or o lactin secretion(1012).The tonie inhibitory effect of nor- centration of serotonin and an elevation of its metabolite epinephrin ikely mediated by adrenergic receptors 5-hydroxyindoleace simultaneousl with the re 00).0n the pr tho ough th ssed by surgical or chemical( pimedw"emrlornteaneee 986).it e mod that sor nin fo pathways (1003 suekling-induced prolactin release 5-Hydroxvtryotophan Blockade of central norepinephrine biosynthesis does not n release requires an intact neurointer by o in ucleus (PVN th anterior pituitary hormone secretion are scarce.Although ohan-or serotonin agonist-induced inere of pr olactir the selective blockade of epinephrine biosynth is in the on has also been demonstrated (104 105.107 CNS blocks th steron ced H surg 1200) data st m1 ed h rg pa NMT(17 On the basis of these obs vations enin phrine doe e not site where s otonin exerts its p rolactin-reles because sero nin elevates prolactin more or less inde How the porta tral adr chanis ed in n ind and lation of nrolactin secretion More recently by using light phan can further increase olasma pro inin rats pre and electron microscopic tech treated with either g-MDT.the inhibitor of the niques. mmunore s on ctive dopamine or reserpine,a dopamine-de- cell g age th nating in the mhological hasis for the modulation of matic region are imnortant in the ulation of nrolactir secretion,especially in generating the estrogen-induced seems quite conceivable that adrenergi on.me urge of ovane tomized rats (921) Howeve or epme phrine. 0L4 in st ays at tons functional context of the imm tochemical findings ranhe or s does not affect suck (775,805)is still undefined. ling-induced or the high afternoon episodic prolactin C)SERO Although ceptor for ser bursts lac ung rats 84 D3. r10 of he pit the the c ser vitro (999 1000)sug sting that it functions as a neun of one or the other in the mediation of the prolactin transmitter rather than a neurohormone.It seems that the erotonin is still superficially uderstood dorsal raphe nucleus is the main source of the ascending and 5HTc seroto n recept agonists in erg lactin 6)651 n vivo (1 cleus in the mediation of rotonin (5-hydroxytrypamine) or its precursor 5-hy- leas has been confirmed (104.105).It has been shown droxytryptophan res in an in se of plasma prola a selective lesion of the PVN,prolactin releas Mn leve as mn n ec recept p affecting prolactin secretion in intact rats (97 reduces significantly reduced.where as there is no cha prolactin release in estrogen-primed rats (260 313)as lactin nse induced by the 5HTL receptor agonist well as completely blocks suckling-induced release of 106. 107).The atter observation that othe a bl SVI a role in mediation of the cursor of s oto nursing (972).A low dose of the serotonin-receptor dicated clearly that endogenous histamine has a stimula blocker methysergide has also been shown to abolish the tory influence on prolactin secretion(1780).For instance
ical data indicated a tonic inhibitory influence of central noradrenergic systems on basal or estradiol-induced prolactin secretion (1012). The tonic inhibitory effect of norepinephrine is likely mediated by a1-adrenergic receptors (400). On the other hand, the proestrous surge of prolactin secretion and stress-induced prolactin release is suppressed by surgical or chemical (6-hydroxydopamine) impairment of central noradrenergic pathways (1003). Blockade of central norepinephrine biosynthesis does not alter suckling-induced prolactin release in lactating rats (286). Data concerning the role of epinephrine in regulating anterior pituitary hormone secretion are scarce. Although the selective blockade of epinephrine biosynthesis in the CNS blocks the estradiol/progesterone-induced LH surge, the secretion of prolactin is not altered by an inhibitor of phenylethanolamine-N-methyltransferase (PNMT) (1734). On the basis of these observations, epinephrine does not appear to have a major function in regulation of prolactin secretion (1734). However, other pharmacological (911, 1012, 1818) and morphological data (775) suggest that central adrenergic mechanisms are involved in the regulation of prolactin secretion. More recently, by using light and electron microscopic immunocytochemical techniques, PNMT-immunoreactive axon terminals have been detected terminating on the cell bodies and dendrites of dopaminergic neurons in the arcuate nucleus (805), thus providing a morphological basis for the modulation of TIDA neuronal activity by epinephrine. Taken together, it seems quite conceivable that adrenergic modulation, mediated by either norepinephrine or epinephrine, plays an important role in stress-induced prolactin secretion; the functional context of the immunocytochemical findings (775, 805) is still undefined. C) SEROTONIN. Although receptors for serotonin are present in the anterior lobe of the pituitary gland (262, 263), serotonin does not stimulate prolactin release in vitro (999, 1000), suggesting that it functions as a neurotransmitter rather than a neurohormone. It seems that the dorsal raphe nucleus is the main source of the ascending serotonergic pathways involved in the regulation of prolactin secretion (Fig. 6) (551, 1788). Intracerebroventricular or intravenous infusion of serotonin (5-hydroxytrypamine) or its precursor 5-hydroxytryptophan results in an increase of plasma prolactin levels in rats (999, 1085), as well as in humans (919). Moreover, inhibition of serotonin synthesis, while not affecting prolactin secretion in intact rats (972), reduces prolactin release in estrogen-primed rats (260, 313) as well as completely blocks suckling-induced release of prolactin (972). After a block of serotonin synthesis, administration of 5-hydroxytryptophan, the immediate precursor of serotonin, restores the prolactin response to nursing (972). A low dose of the serotonin-receptor blocker methysergide has also been shown to abolish the prolactin response to suckling (600). Suckling results in a rapid (within 5 min) decrease in the hypothalamic concentration of serotonin and an elevation of its metabolite 5-hydroxyindoleacetic acid, simultaneously with the release of prolactin (1181). Although the studies with serotonin receptor antagonists are not always conclusive (986), it can be safely assumed that serotonin facilitates suckling-induced prolactin release. 5-Hydroxytryptophaninduced prolactin release requires an intact neurointermediate lobe (1200) and is blunted by hypothalamic ablation in rats (1341). An essential role of the hypothalamic paraventricular nucleus (PVN) in the 5-hydroxytryptophan- or serotonin agonist-induced increase of prolactin secretion has also been demonstrated (104, 105, 107, 1200). These data suggest hypothalamic target(s) for the ascending serotonergic pathways. However, the hypothalamic dopaminergic neurons do not seem to be the major site where serotonin exerts its prolactin-releasing activity because serotonin elevates prolactin more or less independently of the concentration of dopamine in the portal circulation (1420). Dopamine infusion cannot prevent serotonin-induced prolactin release, and 5-hydroxytryptophan can further increase plasma prolactin in rats pretreated with either a-MpT, the inhibitor of the biosynthesis of dopamine or reserpine, a dopamine-depleting agent (1152). Serotonin afferents terminating in the suprachiasmatic region are important in the regulation of prolactin secretion, especially in generating the estrogen-induced prolactin surge of ovariectomized rats (921). However, pharmacological lesion of the serotonin neurons with 5,7-dihydroxytryptamine (5,7-DHT), either at the dorsal raphe or suprachiasmatic regions, does not affect suckling-induced or the high afternoon episodic prolactin bursts in lactating rats (1284). Within the last decade, several serotonin receptor types have been identified in the CNS, but the specific role of one or the other in the mediation of the prolactin response to serotonin is still superficially understood. 5HT1A, 5HT2A, and 5HT2C serotonin receptor agonists increase plasma prolactin in vivo (108, 1040). More recently, the pivotal role of the paraventricular hypothalamic nucleus in the mediation of serotonin-induced prolactin release has been confirmed (104, 105). It has been shown that after a selective lesion of the PVN, prolactin release induced by a 5HT2C receptor agonist is completely prevented, and the stimulatory effect of the 5HT2A agonist is significantly reduced, whereas there is no change in prolactin response induced by the 5HT1A receptor agonist (106, 107). The latter observation suggests that other structures may also have a role in the mediation of the serotonin-induced prolactin response. D) HISTAMINE. Early pharmacological experiments indicated clearly that endogenous histamine has a stimulatory influence on prolactin secretion (1780). For instance, 1548 FREEMAN, KANYICSKA, LERANT, AND NAGY Volume 80
PROLACTIN 1549 intracerebroventricular iniection of histamine incre 2.Acetulcholine prolactin secretion from male or ovariectomized estradi- ol-primed rats(59,456,458,460,1044,1484),whereas H1 cetvlcholine receptor acti histamine receptor antagonists block s ses p klng-or stress prola (59,64 sideration of the rapid deactivation of acetylcholine by her than 457 ne rves a neu 460.1468).Although the 26 pr of the receptors mediatine histamine erects on prolac tin secretion is not clear,it seems that histamine may Cholinergic stimulation by systemic or intracerebro affect prolactin secretion predominantly through H2 re- ventricular administration of cholinergic agonists causes In se ceptor activation (58)and that the effects of Hl antago- m prolactin nists on prolactin sec ely du xtent rini vent suckling-or estradiol to a heretol ds induced prolactin secretion(58.180,1696).It is generally assume is little douht that the affa that the inhibitory effect of acetylcholine and its of hie agonist is me ugh the stimulation of TIDA neu prolactin secretion is mediated through the cNs (960 962,1580).Indeed,a wide variety of histaminergic com- rons pounds show little direct effect on the pituitary gland vent the morphine-induced incr (58,1780,1879).Because the histamine-induced r e in (1261).since momhine is known to affect prolactin secre prolactin secretio in dop oy decre ing TIDA activity (472. 42,1836).Acetyl in po 6 of d the h TIDA are the which is obviously inconsistent with the prima targets for a central histaminergic influence induced decrease of prolactin secretion(662,665,1043) On the other hand.histamine-stimulated prolactin se The atter observation indicates that in addition to the cretion may not be mediated by an inhibition of TIDA hypotha pami systems systems after all,sine intracerebroventricular injec lacti are omon targets of chol nergic mod on of pro tion of his hile producing a do enden tin secretion, (DOPAC tration or -DOPA accumulation)in the 3.Neuropeptides median eminence (557)Although the latter results cast TRE some doubt on the direct histaminergic influence on mone (TSH)se retion from pituitary cells (1566)Subse TIDA neurons,it still seems likely that a histamine dopamine interaction at the hypoth quently,TRH has been shown to stimulate prolactin alamic level is part releas from la totrophs ich h in a dose-dependent manner ua hi distributed ir nable of m lease of the CNS (774.1186).Most of the TRH-immun m053 955)noreninenhrine (554)serotonin (555 875)endog perikarya projecting to the median eminence are in the enous opioids (958),and dopamine (1571),all of which parvicellular subdivision of the paraventricular nucleusof the 101 are involved in the e regulation of prolactin secretion hypothalamus 2 118 to nyp role the central histaminergic system nt o r1120 on lactotrophs (763).These data would suggest that al th 1317 most all of the requirements for considering TRH as a PRF clusively localized in the mammillary nuclei (16,8 in a physiological context are 1376)inhibits stress.induced prolactin secretion in male rats (961).In addition,inhibition of histamine in normal male or lactating female rats (681 1419.148D synthesis and release by activation of central presyn However,the release of prolactin and TSH is dissociated aptic H3 receptors(90,603)diminishes stress-induced ISH secretion is found to be only modestly affected prolactin secretion (961,1656) (1481)or unaffected (1615)by stress or suckling,whereas
intracerebroventricular injection of histamine increases prolactin secretion from male or ovariectomized estradiol-primed rats (59, 456, 458, 460, 1044, 1484), whereas H1 histamine receptor antagonists block suckling- or stressinduced prolactin release (59, 644, 1044). On the other hand, H2 histamine antagonists rather than H1 block exogenous histamine-induced prolactin secretion (58, 457, 460, 1468). Although the precise pharmacological profile of the receptor(s) mediating histamine effects on prolactin secretion is not clear, it seems that histamine may affect prolactin secretion predominantly through H2 receptor activation (58) and that the effects of H1 antagonists on prolactin secretion observed earlier are likely due to a heretofore uncharacterized nonspecific effect of these compounds (1780). There is little doubt that the effect of histamine on prolactin secretion is mediated through the CNS (960, 962, 1580). Indeed, a wide variety of histaminergic compounds show little direct effect on the pituitary gland (58, 1780, 1879). Because the histamine-induced rise in prolactin secretion coincides with a decrease in dopamine concentration in portal blood (622), it seems likely that the neuroendocrine dopaminergic neurons in the hypothalamus, especially the TIDA system, are the primary targets for a central histaminergic influence. On the other hand, histamine-stimulated prolactin secretion may not be mediated by an inhibition of TIDA systems after all, since intracerebroventricular injection of histamine, while producing a dose-dependent increase of prolactin secretion, does not affect the biochemical indexes of dopaminergic neuronal activity (DOPAC concentration or L-DOPA accumulation) in the median eminence (557). Although the latter results cast some doubt on the direct histaminergic influence on TIDA neurons, it still seems likely that a histaminedopamine interaction at the hypothalamic level is part of the neural mechanism by which histamine modulates prolactin secretion (558). In addition, histamine, through a presynaptic H3 histamine receptor (1571), is capable of modulating the release of vasopressin (953, 955), norepinephrine (554), serotonin (555, 875), endogenous opioids (958), and dopamine (1571), all of which are involved in the regulation of prolactin secretion. The role of the central histaminergic system in regulating prolactin secretion was corroborated by the finding that bilateral lesion of the posterior hypothalamus (1317), which destroys histaminergic neurons exclusively localized in the mammillary nuclei (16, 838, 1376), inhibits stress-induced prolactin secretion in male rats (961). In addition, inhibition of histamine synthesis and release by activation of central presynaptic H3 receptors (90, 603) diminishes stress-induced prolactin secretion (961, 1656). 2. Acetylcholine In GH3 cells, muscarinic acetylcholine receptor activation decreases prolactin secretion (1885). With the consideration of the rapid deactivation of acetylcholine by the omnipresent cholinesterases, it seems unlikely that acetylcholine of hypothalamic origin subserves a neuroendocrine role as a regulator of prolactin secretion (276). Cholinergic stimulation by systemic or intracerebroventricular administration of cholinergic agonists causes a decrease in serum prolactin concentration (662, 665, 1043). Moreover, cholinergic agonists (nicotinic and, to a lesser extent, muscarinic) prevent suckling- or estradiolinduced prolactin secretion (58, 180, 1696). It is generally assumed that the inhibitory effect of acetylcholine and its agonist is mediated through the stimulation of TIDA neurons (504, 665, 1696, 1885). This assumption is further supported by the finding that acetylcholine agonists prevent the morphine-induced increase of prolactin secretion (1261), since morphine is known to affect prolactin secretion by decreasing TIDA activity (472, 742, 1836). Acetylcholine administered intracerebroventricularly decreases the concentration of dopamine in portal blood (622), which is obviously inconsistent with the acetylcholineinduced decrease of prolactin secretion (662, 665, 1043). The latter observation indicates that in addition to the hypothalamic neuroendocrine dopaminergic systems, there are other targets of cholinergic modulation of prolactin secretion. 3. Neuropeptides A) TRH. TRH was originally isolated as a hypophysiotrophic factor that stimulates thyroid-stimulating hormone (TSH) secretion from pituitary cells (1566). Subsequently, TRH has been shown to stimulate prolactin release from lactotrophs in a dose-dependent manner both in vitro and in vivo (178, 202, 1723). TRH-like immunoreactivity is widely distributed in the CNS (774, 1186). Most of the TRH-immunopositive perikarya projecting to the median eminence are in the parvicellular subdivision of the paraventricular nucleus of the hypothalamus (227, 724, 774, 1015, 1186). TRH is secreted into hypophysial stalk blood (520, 553), and its receptor is present on pituitary cells (1129), specifically on lactotrophs (763). These data would suggest that almost all of the requirements for considering TRH as a PRF in a physiological context are satisfied. TRH can efficiently stimulate pituitary prolactin secretion in vivo in estrogen-primed male rats (1419) but not in normal male or lactating female rats (681, 1419, 1481). However, the release of prolactin and TSH is dissociated. TSH secretion is found to be only modestly affected (1481) or unaffected (1615) by stress or suckling, whereas October 2000 PROLACTIN 1549
1550 FREEMAN,KANYICSKA,LERANT,AND NAGY Volume 80 es to the same stimuli are quite signifi- act Injection of specific antibodies to immunoneutralize bisphosphate to yield inositol trisphosphate and diacyl hypophysiotrophic (passiv immunization) glycerol (57,529,807,1684).Inosito. trisphosphate medi widely calciun hs (617 Di (069 and ckling-ind aseC（467 prolactin response (405).However,TRH antiserum only lates voltas nsitive caleium channels resulting inin weakly reduces prolact tin-releasing activity of the hypo creased nflux. and thus enhances prolactin 1704),suggesting tha t TRH is not exoc (56 the R万 icted as rapidly stimula hin releasing hormon TRH may also affect prolactin se first phas e fast elevation within 30 s followed by a lower tion by acting within the CNS It has been reported that secondary phase (17,924).On the Das in tumoro pro M is the n i tions from the paraventricular nucleus to the arcuate cium more ecifically it has been s ed that inosito nucleus have bee n detected (227),there is a morpholog trisphosphate induces an initial rapid release of calcium cal a direct TRH/dopamine interaction at the that media s the nrst phase o hypo e an t the cellular level argue for a role for f dia TRH in the control of prolactin s etion TRH horvlation of a volta ated calcium chan in lactotrophs have been detected by Hinkle and Tashjian nel.and ultimate entrance of calc um from extracellular (763) With H rces(215,61 -61 sing sele an (1917 Priman of rat nituitary cells were stained with an antibody to the native TRH receptor and with a influx and/or transduction pathways linked to calcium analog of TRH mine-TRI infux are m prola d2%aa sp 0 cultures.Lactotrophs and thy nhs ace ed for 90 Nwer data have revealed mor of the snatiotemn cells that were labeled with rhodamine-conjugated ral complexity of the cytoplasmic Ca2 changes.For in occasional lactotrophs and thyro stance membran capacitance measurements to 104 0 by m data imply that some of the functional was found that TRH promotes exe cvtosis through thre among lactotrophs(190,298,773,830,1625,1708,1814 distinct stages (563)First within 30 s TRH transiently rom a differer ntial expre on of the TRH evokes exocytosis that is independen f membrane de th de extracellular onstrated convincingly that the TRH rec or under sitive ond within a min of evr ligand-directed endocytosis in normal cells (1917). TRH TrH facilitates depolarization evoked exocyt re ptors were d on the su e of cells before while nhib ing the voltage-gated calcium current. anep0 and furthe calcium channel current thro gh a n rotein kinase C-de cells were incubated with TRH at 37C receptors were pendent mechanism (564). found in intracellular vesicles in both lactotrophs and inally,there is a large amount of literature showing ophs,and rho a that 101 or tran once bound to the re tos CTP. olactin binding proteins(1002),which have been characterized as tion.Although the data are convincing,the interpretation either G.(943).G.or Gu (807.Activation of G.or Gu.in must be approached with caution.since it is unlikely that
prolactin responses to the same stimuli are quite signifi- cant (1481, 1615). Injection of specific antibodies to immunoneutralize hypophysiotrophic factors (passive immunization) is widely used to confirm the physiological relevance of a given factor. TRH antiserum can suppress the proestrous prolactin surge (963) and attenuate the suckling-induced prolactin response (405). However, TRH antiserum only weakly reduces prolactin-releasing activity of the hypothalamic extract (203, 1704), suggesting that TRH is not the only authentic PRF. In addition to its well-established role as a prolactinreleasing hormone, TRH may also affect prolactin secretion by acting within the CNS. It has been reported that central administration of TRH inhibits prolactin secretion (1342), most likely through stimulation of TIDA neurons (836, 1342). Because TRH-immunopositive neural projections from the paraventricular nucleus to the arcuate nucleus have been detected (227), there is a morphological basis for a direct TRH/dopamine interaction at the hypothalamic level. Many studies at the cellular level argue for a role for TRH in the control of prolactin secretion. TRH receptors in lactotrophs have been detected by Hinkle and Tashjian (763). With the use of modern immunocytochemical approaches, TRH receptors have been found on the plasma membrane as well as intracellularly in rat lactotrophs (1917). Primary cultures of rat pituitary cells were stained with an antibody to the native TRH receptor and with a bioactive, fluorescent analog of TRH, rhodamine-TRH. Rhodamine-TRH specifically stained 86% of lactotrophs and 21% of nonlactotrophs from primary pituitary cell cultures. Lactotrophs and thyrotrophs accounted for 90% of cells that were labeled with rhodamine-conjugated TRH, but there were occasional lactotrophs and thyrotrophs that did not show detectable staining with antireceptor antibodies or with rhodamine-TRH (1917). These data imply that some of the functional heterogeneity among lactotrophs (190, 298, 773, 830, 1625, 1708, 1814, 1921) may result from a differential expression of the TRH receptor. With the use of TRH receptor immunocytochemistry and rhodamine-labeled TRH, it has been demonstrated convincingly that the TRH receptor undergoes ligand-directed endocytosis in normal cells (1917). TRH receptors were localized on the surface of cells before TRH exposure, and rhodamine-TRH fluorescence was confined to the plasma membrane when TRH binding was performed at 0°C, where endocytosis is blocked. When cells were incubated with TRH at 37°C, receptors were found in intracellular vesicles in both lactotrophs and thyrotrophs, and rhodamine-TRH was rapidly internalized into endosomes at elevated temperatures (1917). Once bound to the receptor, TRH activates GTPbinding proteins (1002), which have been characterized as either Gs (943), Gq or Gll (807). Activation of Gq or Gll, in turn, activates membrane-bound phospholipase C that catalyzes the hydrolysis of phosphatidylinositol 4,5- bisphosphate to yield inositol trisphosphate and diacylglycerol (57, 529, 807, 1684). Inositol trisphosphate mediates the mobilization of nonmitochondrial calcium in lactotrophs (617). Diacylglycerol, in turn, activates calcium-dependent protein kinase C (467) which phosphorylates voltage-sensitive calcium channels resulting in increased Ca21 influx, and thus enhances prolactin exocytosis (563, 564, 747). TRH was originally depicted as rapidly stimulating a biphasic pattern of prolactin secretion characterized by a first phase fast elevation within 30 s followed by a lower amplitude sustained secondary phase (17, 924). On the basis of studies in tumorous cell lines, it has been suggested that this pattern of prolactin secretion parallels and is the result of similar changes in intracellular calcium. More specifically, it has been suggested that inositol trisphosphate induces an initial rapid release of calcium from intracellular stores that mediates the first phase of prolactin secretion while the second phase is the consequence of diacylglycerol-induced activation of protein kinase C, phosphorylation of a voltage-gated calcium channel, and ultimately entrance of calcium from extracellular sources (215, 614–616, 722, 971). However, using selective pharmacological depletion of intracellular calcium stores or blockade of voltage-sensitive calcium channels, it was suggested that in normal pituitary cells, calcium influx and/or transduction pathways linked to calcium influx are more important to prolactin secretion in response to TRH than is liberation of Ca21 from cytoplasmic stores (1558). Newer data have revealed more of the spatiotemporal complexity of the cytoplasmic Ca21 changes. For instance, using membrane capacitance measurements to study TRH-induced modulation of exocytosis by metabolically intact perforated patch-clamped rat lactotrophs, it was found that TRH promotes exocytosis through three distinct stages (563). First, within 30 s, TRH transiently evokes exocytosis that is independent of membrane depolarization and extracellular calcium influx, but is likely driven by Ca21 released from inositol trisphosphate-sensitive intracellular pools. Second, within 3 min of exposure, TRH facilitates depolarization-evoked exocytosis while inhibiting the voltage-gated calcium current. Finally, after 8 min, TRH further enhances depolarizationevoked exocytosis by increasing high voltage-activated calcium channel current through a protein kinase C-dependent mechanism (564). Finally, there is a large amount of literature showing that transient dopamine antagonism (716–721) or transient dopamine withdrawal (1132–1134, 1136–1138) magnifies the stimulatory effect of TRH on prolactin secretion. Although the data are convincing, the interpretation must be approached with caution, since it is unlikely that, 1550 FREEMAN, KANYICSKA, LERANT, AND NAGY Volume 80
PROLACTIN 1551 under physiological conditions.dopaminergic neurons be- rotransmitter may play a stimulatory role in regulating come totally quiescent.It seems more likely that the TIDA neurons (1919),which,in tumn,would convey an lactotroph is exposed to diminishing concentrations of inhibitory influence on prolactin secretion C)V ssin is sy d stimulated prolactin se retion has vet to be determin the nosterior division of the paraventricular and the su B)oxrTocIN.Oxytocin is synthesized in the PVN and praoptic nuclei (1657).In addition,vasopressin immuno supraoptic nucleus (SON)and axonally transported to the reactivity is also found in the parvicellular neurons of the until 165e the median eminence already form syna antic boutons median eminence en route to the posterior lobe of the which contact the capillary loons of the median emi pituitary gland (782),whereas the parvicellular neurons nence.Indeed,oxytocin release into the long portal ves project directly to the extemal zone of the median emi 62 ove. on the prin ed fron zone of the anterior lobe also p ssin can reach the anterior lobe of the pituitar gland from both sources through the long or the shor The stimulatory effect of neurointermediate lobe ex portal systems (673). ra has t arly ind ted that dis reted into the hu of the no al lob ely alte husial n 10-15 times higher concentrations than found in the pe lactin secretion (450.829.1283).Bilateral anterior hyp ripheral circulation (620),and high-affinity receptors re ne oxytocin re ceptors re pre in th pa and officac Iow (827 al lobe (811) (145)an0 1537).and the definitive role of oxytocin as a neurohy prevent suckling-induced prolactin release in oxytocin- pophysial PRF requires further attentior substituted lactating animals.In addition,there is no Severa udie hav tha ng-induce ay D of tho is of tion (1372 1542)Although a large dose of oxytocin in sin (829.1283,1283).Moreover, passive immuniza duces a rise in plasma prolactin in male or ovariectomized tions against arginine vasopressin(1283),or the glycopep female rats 087,t1 ct prol secretion tide moiety of the sopress n-ne ophysin- ow n rat 76) well as st nduced secretion of prolactin in male rats e data suggest that vasonre ssin and relatec (1087.1235.1243).Attempts to antagonize the action of peptides play a significant role in regulating prolactin Ited in con ting nd redu or by n 537).on the other hand.ini tion of a release prolactin in vitro (734.1616).There are arginin specific oxvtocin antagonist.which blocks suckling-in in receptors in the rat anterior pituitary (47 duced mill eje ction,does not alter cor 957 and argini t ent in high concen S67.】 ver,t en yto n porta 1(192 ophysi g th Mo ove ism plocks the endog te prolactin release from the anterior lobe but no stimulatory rhythm (73.74.76)that governs prolactin through a direct effect on the pituitary gland(1618).The secretion in female rats (71).Similarly oxytocin antag 39-amino acid glycopeptide comprsing the COOH termi a a pro ecreno under some(but not all)physiological state ctin release from cultured pituitary cels Passive In addition to its role as neurohormone,the possibil- immunization studies support the stimulatory role of this ity of central effects of oxytocin should also be taken into peptide in the control of prolactin secretion (1276).De- consideration (1309,1310).For instance,oxytocin as neu spite som controversial and inexplicable results,vaso
under physiological conditions, dopaminergic neurons become totally quiescent. It seems more likely that the lactotroph is exposed to diminishing concentrations of dopamine rather than a complete absence of dopamine. The effect of a reduction of dopamine exposure on TRHstimulated prolactin secretion has yet to be determined. B) OXYTOCIN. Oxytocin is synthesized in the PVN and supraoptic nucleus (SON) and axonally transported to the neural lobe where it is briefly stored until release from terminals. Axons of the oxytocin neurons passing through the median eminence already form synaptic boutons, which contact the capillary loops of the median eminence. Indeed, oxytocin release into the long portal vessels has been well-established (620, 1320). Moreover, short portal vessels connecting neural lobe and the inner zone of the anterior lobe also provide a potential route for delivering oxytocin to the adenohypophysis. The stimulatory effect of neurointermediate lobe extracts on prolactin release has been thought to be partially due to the influence of oxytocin in the extracts (1537). Oxytocin is secreted into the hypophysial portal blood in 10–15 times higher concentrations than found in the peripheral circulation (620), and high-affinity receptors resembling the uterine oxytocin receptors are present in the anterior lobe. However, the prolactin-releasing potency and efficacy of oxytocin in vitro are rather low (827, 1537), and the definitive role of oxytocin as a neurohypophysial PRF requires further attention. Several studies have previously indicated that, at least in certain experimental situations, oxytocin may be involved in the stimulatory regulation of prolactin secretion (1372, 1542). Although a large dose of oxytocin induces a rise in plasma prolactin in male or ovariectomized female rats (1087), it fails to affect prolactin secretion in lactating rats. In contrast, subcutaneous administration of a low dose of oxytocin induces a reduction in basal as well as stress-induced secretion of prolactin in male rats (1087, 1235, 1243). Attempts to antagonize the action of endogenous oxytocin in vivo have also resulted in con- flicting data. Passive immunization with oxytocin antisera delays and reduces prolactin surges induced by suckling or by estrogen (1537). On the other hand, injection of a specific oxytocin antagonist, which blocks suckling-induced milk ejection, does not alter concomitant prolactin release (867). However, treatment with an oxytocin antagonist prevents the proestrous surge of prolactin (867). Moreover, oxytocin antagonism blocks the endogenous stimulatory rhythm (73, 74, 76) that governs prolactin secretion in female rats (71). Similarly, oxytocin antagonism blocks mating-induced prolactin secretion (74). Therefore, it seems likely that oxytocin may act as a PRF under some (but not all) physiological states. In addition to its role as neurohormone, the possibility of central effects of oxytocin should also be taken into consideration (1309, 1310). For instance, oxytocin as neurotransmitter may play a stimulatory role in regulating TIDA neurons (1919), which, in turn, would convey an inhibitory influence on prolactin secretion. C) VASOPRESSIN. Similar to oxytocin, vasopressin is synthesized by the magnocellular neurons located mainly in the posterior division of the paraventricular and the supraoptic nuclei (1657). In addition, vasopressin immunoreactivity is also found in the parvicellular neurons of the medial division of the paraventricular neurons (1657). The axons of the magnocellular neurons pass through the median eminence en route to the posterior lobe of the pituitary gland (782), whereas the parvicellular neurons project directly to the external zone of the median eminence to terminate on the primary capillary bed from which the long portal vessels arise (1657). Therefore, vasopressin can reach the anterior lobe of the pituitary gland from both sources, through the long or the short portal systems (673). Previous studies have clearly indicated that disturbances in the water and electrolyte regulation at the level of the neural lobe severely alters adenohypophysial prolactin secretion (450, 829, 1283). Bilateral anterior hypothalamic deafferentation behind the optic chiasm or lesion of the PVN interrupting the paraventriculo-, and supraoptico-hypophysial tract (948), or denervation of the neural lobe (1811) result in diabetes insipidus (145) and prevent suckling-induced prolactin release in oxytocinsubstituted lactating animals. In addition, there is no suckling-induced hormone response in homozygous Brattleboro mothers suffering diabetes insipidus due to the genetic failure of the biosynthesis of arginine vasopressin (829, 1283, 1283). Moreover, passive immunizations against arginine vasopressin (1283), or the glycopeptide moiety of the vasopressin-neurophysin-glycopeptide precursor, with a highly specific antiserum attenuates the suckling-induced rise of plasma prolactin (1276). Taken together, these data suggest that vasopressin and related peptides play a significant role in regulating prolactin secretion. Although arginine vasopressin induces prolactin release in vivo (1372, 1785, 1809), it does not effectively release prolactin in vitro (734, 1616). There are arginine vasopressin receptors in the rat anterior pituitary (47, 957), and arginine vasopressin is present in high concentration in portal blood (1926). In addition, neurophysin II, the midportion of the prepro-vasopressin molecule, can stimulate prolactin release from the anterior lobe but not through a direct effect on the pituitary gland (1618). The 39-amino acid glycopeptide comprising the COOH terminus of the vasopressin precursor has been reported to stimulate (1276), inhibit (1567), or have no effect (829) on prolactin release from cultured pituitary cells. Passive immunization studies support the stimulatory role of this peptide in the control of prolactin secretion (1276). Despite some controversial and inexplicable results, vasoOctober 2000 PROLACTIN 1551
1552 FREEMAN,KANYICSKA,LERANT,AND NAGY Volume 80 factors role as hyp pla tuitary prolactin secretion (50,952) ducing ntral stimulatory influences on the pituitary lac asopressi rts its physiological effects by acti totrophs(1313,1506),particularly those e which are con vating at I t tw veyed by serotonergic mechanisms (891) VIP als ne regulator oI pro a( h the v were originally found in the renal tubular epithelial cells (857).The V:couples to the phosphoinositide signaling vivo immunoneutralization is not clear As to what pr 8570.Th V2 receptors acuval portion of the reduction of prolactin release by VIP anti serum is due to the neutra zation of VIP of hypothalamic gh V (50 952).although other ongin vasopressin recentor(s)may also VIP rolactin play a role (954.955) tha veral biologi disn rsed pituitary cells (538).The relative contribution nd th of PHI and VIP to the control of prolactin secretion re- quires further investigation tuitary adenylyl cyc entide (pacap) ystem of PACAP-38 significantly have been shown to significantly affect pituitary prolactin eC0252 This effect of PACAP on etion is like vas the the rela d to its stimulation of prolactin gene expression ntricular nuelei and the median em inence(162,380,1010,1191,1399,1638).PHI and VIP are (212,352,1815)through a protein kinase A-mediated path- 48and (353) Surprisingly,PACAP-3 dose-dep synthesized from a comm are ho b blood (1608). The e new relative in this family is PACAP (1208).PACAP is a VIP-like hypothalamic trasting effects of PACAP-38 on pituitary prolactin re lease ring in twe PACAP-27 Carly observations already indicated that,in addi with the are strong to t VIp and can induce a very strong a 1823H the in cultured anterior pituitary cells (1208)by binding to the ntide family or high-affinity recepto 16 in vitr o(917,1512,159182nre VIP,but n or PHI VIp recentors found in anterior nituitan 7cels(125) cre suggesting specific 01 stimulates prolactin release in vitro between 10 1 M concentrations in a dose-rel: 1608 610 Both pacap and viP when administered intracere hi broventricularly to conscious ovariectomized estradiol general circulation (1528),which is sufficient to stim ulate implanted female rats,stimulate TIDA activity (813 prolactin release from pituitary cells in vitro.These find ver,the efects of t on pro ings sugges that VIP may be an important mediator of o)Th dim situa on prolactin secretion is consistent with its stimulation of (891 1611)stimulation of hypothalamie dopaminergic activity.It seems,however prolactin release by ether stress is completely blocked that in the case of VIP,an additional unknown mechanisn (1611).whereas s ckling-induced prolactin response is into play perh ibite 4 5.ht 154)列 olactin release (8al)while PACAP also inhibits nrolactin secretion (1560)hy actin munization with antisera to either ViP or pHI results in within the medial basal hypothalamus (40).However,in only a minimal effect(891).Taken together,these data anesthetized male rats,central administration of
pressin, its precursor, its specific neurophysin, or other factors associated with diabetes insipidus may affect pituitary prolactin secretion (50, 952). Vasopressin exerts its physiological effects by activating at least two different receptors: the V1 (“vascular”) vasopressin receptor is most abundant in vascular smooth muscle cells and hepatocytes, whereas the V2 receptors were originally found in the renal tubular epithelial cells (857). The V1 couples to the phosphoinositide signaling pathway, whereas the V2 receptors activate adenylate cyclase (857). The arginine vasopressin-induced increase in prolactin secretion is mediated mainly through V1 (50, 952), although other vasopressin receptor(s) may also play a role (954, 955). D) THE SECRETIN/VIP FAMILY. Several biologically active peptides of the secretin/VIP family, such as VIP, peptide histidine-isoleucine (PHI) and the recently discovered pituitary adenylyl cyclase-activating polypeptide (PACAP) have been shown to significantly affect pituitary prolactin secretion. VIP was originally isolated from porcine small intestine (1527). Its presence was then demonstrated in the hypothalamic paraventricular nuclei and the median eminence (162, 380, 1010, 1191, 1399, 1638). PHI and VIP are synthesized from a common precursor (848) and are homologous to each other (1709, 1727). Both peptides are secreted in equimolar amounts into hypophysial portal blood (1608). The new relative in this family is PACAP (1208). PACAP is a VIP-like hypothalamic peptide occurring in two forms, PACAP-27 and the COOH-terminally extended PACAP-38. These peptides share strong sequence homology (68%) with the NH2-terminal portion of VIP and can induce a very strong accumulation of cAMP in cultured anterior pituitary cells (1208) by binding to high-affinity receptor sites (1623). VIP can stimulate prolactin release both in vivo and in vitro (917, 1512, 1591, 1823) through a direct action on VIP receptors found in anterior pituitary cells (125). VIP stimulates prolactin release in vitro between 1027 and 10210 M concentrations in a dose-related manner (1608– 1610). Moreover, it is detected in the portal blood in a concentration ;10 times higher than that found in the general circulation (1528), which is sufficient to stimulate prolactin release from pituitary cells in vitro. These findings suggest that VIP may be an important mediator of prolactin release in different physiological situations. Moreover, when passive immunization is performed to neutralize VIP in the plasma (891, 1611), stimulation of prolactin release by ether stress is completely blocked (1611), whereas suckling-induced prolactin response is only partially inhibited (4). Simultaneous administration of VIP and PHI antisera completely blocks 5-hydroxytryptophan-induced prolactin release (891), while passive immunization with antisera to either VIP or PHI results in only a minimal effect (891). Taken together, these data suggest that endogenous VIP-like peptides likely play a role as hypothalamic neurohormones (i.e., PRF) by transducing central stimulatory influences on the pituitary lactotrophs (1313, 1506), particularly those which are conveyed by serotonergic mechanisms (891). VIP also plays a role as an autocrine regulator of prolactin secretion (715, 1275), and as such, can be released by the lactotrophs themselves. Therefore, the source of VIP affected by in vivo immunoneutralization is not clear. As to what proportion of the reduction of prolactin release by VIP antiserum is due to the neutralization of VIP of hypothalamic origin remains to be established. Similar to VIP, PHI can stimulate prolactin release in the freely moving rat (892, 1343, 1873) as well as from dispersed pituitary cells (1538). The relative contribution of PHI and VIP to the control of prolactin secretion requires further investigation. Systemic injection of PACAP-38 significantly and dose-dependently stimulates pituitary prolactin in both male (1025) and nonsuckled lactating female rats (67). This effect of PACAP on prolactin secretion is likely related to its stimulation of prolactin gene expression (212, 352, 1815) through a protein kinase A-mediated pathway (353). Surprisingly, PACAP-38 dose-dependently inhibits prolactin release in both monolayer cultures (858) and reverse hemolytic plaque assay (858) of rat pituitary cells. Thus in vitro and in vivo experiments provide contrasting effects of PACAP-38 on pituitary prolactin release. Early observations already indicated that, in addition to their direct action on lactotrophs, there is a hypothalamic site of action for some of these peptides (849, 917, 1823). However, there is no consensus as yet concerning the central effects of the secretin/VIP peptide family on prolactin secretion. For instance, preoptic injection of VIP, but not of secretin or PHI, stimulates prolactin secretion (123), suggesting specific actions of VIP on the preoptic mechanisms governing prolactin secretion in ovariectomized rats (123). Both PACAP and VIP, when administered intracerebroventricularly to conscious ovariectomized estradiolimplanted female rats, stimulate TIDA activity (813). However, the effects of these peptides on prolactin secretion are opposite: whereas PACAP inhibits, VIP stimulates prolactin secretion (813). The inhibitory effect of PACAP on prolactin secretion is consistent with its stimulation of hypothalamic dopaminergic activity. It seems, however, that in the case of VIP, an additional unknown mechanism comes into play [perhaps an increase of PRF from hypothalamic sources (74, 1547)] that would override the consequence of TIDA activation. Interestingly, in sheep, PACAP also inhibits prolactin secretion (1560) by acting within the medial basal hypothalamus (40). However, in anesthetized male rats, central administration of 1552 FREEMAN, KANYICSKA, LERANT, AND NAGY Volume 80