Histaminergic regulation of prolactin secretion: involvement of tuberoinfundibular dopaminergic neurons

It has been shown that histamine (HA) stimulates prolactin (PRL) secretion via H2 receptors following intra-cerebroventricular infusion and via H1 receptors following systemic (intra-arterial) infusion. Since the effect of HA appears to be exerted at a suprapituitary level, we investigated the involvement of the tuberoinfundibular dopaminergic (TIDA) system in HA-induced PRL secretion in urethane-anesthetized male rats. HA infused intracerebroventricularly (30 micrograms) or intra-arterially (420 micrograms) decreased the dopamine (DA) concentration in pituitary portal blood by 30 and 23%, respectively. Blockade of DA receptors by pimozide did not prevent the stimulation of PRL secretion induced by intracerebroventricular infusion of HA or the H2 receptor agonist dimaprit. Furthermore, during DA receptor blockade intracerebroventricular infusion of the H1 receptor agonist 2-thiazolylethylamine inhibited PRL secretion. In contrast, pimozide prevented the stimulation of PRL secretion induced by intra-arterial infusion of HA and the H1 receptor agonist 2-thiazolylethylamine. In fact, under these conditions intra-arterial infusion of HA or the H2-receptor agonist dimaprit inhibited PRL secretion. During treatment with alpha-methyl-p-tyrosine, which reduced the hypothalamic DA content by 50%, HA infused intracerebroventricularly stimulated PRL secretion, while HA infused intra-arterially inhibited the secretion, which is in accordance with the results obtained during pimozide treatment. Cholinergic blockade by atropine did not prevent the HA-induced PRL release, excluding the possibility that the observed effect of pimozide is due to its anticholinergic property. We suggest that intracerebroventricular infusion of HA by activation of H2 receptors may stimulate PRL secretion partly via inhibition of the TIDA system and partly via other mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immobilization stress and prolactin secretion in male rats. Possible roles of dopamine and TRH.

Immoblization stress had a biphasic effect on serum prolactin levels: the early short stimulatory phase followed by a long inhibitory phase in male rats. Stress induced the rise in serum prolactin without concomitant increase in serum TSH levels which declined during the immoblization for 300 min. Other stressors, ether inhalation or formalin s.c. injection, or TSH i.v. injection, which were effective in controls failed to elevate serum prolactin after the 300-min immobilization. Serum TSH responded to TRH after the stress as well. Pimozide, dopamine receptor blocker, was effective in increase of serum prolactin in the stressed rats as well as in controls. In pimozide pretreated rats, elevated serum prolactin levels decrease in 10 min by the immobilization and returned to the preimmobilization levels thereafter which were higher than those in stressed animals without pimozide treatment. It is suggested that TRH is not a physiological PRF in the stress-induced prolactin release and that the dopaminergic system may be activated by the immunoblization stress, resulting in decrease of the prolactin-releasing activity of the pituitary.     

On the presence of a nondopaminergic, peptidergic prolactin release-inhibiting factor in hypothalamic extracts of infantile rats

Crude hypothalamic extracts prepared from brains of 1-day-old rats produced a dose-dependent inhibition of prolactin (Prl) release by adult male hemipituitaries, and to a lesser extent by hemipituitaries of adult ovariectomized (OVX), estrogen-primed rats. These extracts contained 6-fold lower levels of dopamine than adult hypothalami. The inhibitory effect of the adult hypothalamic extracts, contrary to infantile hypothalamic extracts could be blocked by spiroperidol. Digestion of the infantile hypothalamic extracts with pronase totally abolished their Prl release-inhibiting activity, indicating the peptidic nature of this inhibitory substance. In contrast to their effect on Prl release by hemipituitaries, infantile hypothalamic extracts stimulated Prl release from dispersed anterior pituitary cells of OVX estrogen-primed rats, pointing to the importance of estrogen in modulating prolactin release-inhibiting factor (PIF) activity and the possibility that the PIF receptor is trypsin-sensitive.     

Bovine neurophysin II has prolactin-releasing activity in the estradiol-primed male rat

In the course of the search for the prolactin-releasing factor (PRF), we noticed that the posterior pituitary contained strong PRF activity and subsequently traced this activity to that of bovine neurophysin-II (NP-II). NP-II prepared in our lab was judged to be a homogeneous preparation according to Sephadex G-75 gel filtration, DEAE ion exchange chromatography and polyacrylamide gel electrophoresis. While neurophysin-I (NP-I) injections of 100 micrograms/kg and 1,000 micrograms/kg elevated plasma prolactin in estradiol-primed male rats to 30% and 50% over the control value, respectively, NP-II doses of 100, 1,000 micrograms/kg increased plasma prolactin concentration in estradiol-primed male rats to 130% and 170% over the control value, respectively. The lowest dose of NP-II needed to increase plasma prolactin concentration was 10 micrograms/kg. Since neurophysin does not stimulate prolactin release from the ectopic pituitary under the kidney capsule nor from lactotrophs in a primary monolayer culture system, neurophysin is believed to act indirectly on the pituitary, presumably through a neurotransmitter and/or hypothalamic releasing (or inhibiting) factor. We propose that NP-II may be one element in the complex chain of the prolactin-releasing mechanism.     

Evidence that serotonin stimulates a prolactin-releasing factor in the rat.

Methanol extracts of rat plasma resulted in release of prolactin (PRL) from rat hemipituitaries in vitro with a linear log-dose relationship. This prolactin-releasing factor (PRF)-like activity was not altered in plasma from rats treated with bromocryptine or chlorpromazine despite significant suppression and stimulation of plasma PRL levels, respectively. Fluoxetine, a serotonin reuptake inhibitor, plus 5-hydroxytryptophan, the immediate precursor of serotonin, markedly stimulated both plasma PRL and plasma PRF-like activity. Neither fluoxetine, 5-hydroxytryptophan, nor the combination directly stimulated PRL release from rat pituitary tissue in vitro. We conclude that serotonergic stimulation augments PRL release via a PRF.     

Hypothalamic control of prolactin and growth hormone secretion in the pituitary gland of the pigeon and the chicken: in vitro studies

Hypothalamic extracts stimulated the release of prolactin and growth hormone from pigeon and chicken pituitary glands incubated in vitro. Release of hormone was proportional to the amount of hypothalamic extract added. Pituitary glands from "lactating" pigeons released more prolactin and their hypothalami contained more prolactin-releasing activity compared with controls. Partial separation of prolactin releasing activity from growth hormone releasing activity in chicken hypothalamic extract was achieved using gel filtration chromatography. Co-incubation studies in vitro with hypothalamic tissue present showed that prolactin release from the pituitary was inhibited and growth hormone release was stimulated when dopamine was added to the medium. The effects of dopamine were blocked by the antagonist pimozide. The possible existence of hypothalamic releasing and inhibiting factors regulating secretion of prolactin and growth hormone is discussed.     

Failure of dopamine and bromocriptine to affect prolactin release and cell growth in the dopamine receptor-deficient 235-1 clone

The 235-1 clone was recently derived from the 7315a transplantable pituitary tumor and continues to secrete rat prolactin. The cells have a prominent Golgi apparatus which can be stained immunocytochemically for prolactin, but there were no 600–900 nm granules which are characteristic of normal mammotrophs. In a perfused cell-column apparatus, prolactin release from the clone was unchanged by dopaminergic agonists, thyrotropin-releasing hormone and estradiol but stimulated by dibutyryl cyclic AMP. Cellular cyclic AMP content was also not changed by dopamine but was dramatically enhanced by prostaglandin E₁, indicating that at least one hormone-adenylate cyclase coupling mechanism was functional. In radioligand binding studies using the dopamine antagonist [³H]spiperone, no evidence of a dopamine receptor was obtained. The [³H]spiperone binding present was not stereoselective, and exceedingly high concentrations of other ligands were required to displace the binding. In addition, the induction of a prolactin-secreting hard tumor in rats by subcutaneous innoculation of the 235-1 cells failed to induce measurable dopamine receptors associated with the tumor cells.In order to address the possibility that there were functional dopamine receptors on these cells, but that they could not be resolved with either the cell column and cyclic AMP studies or the radioreceptor assay, the clone cells were incubated with 0.1–100 nM bromocriptine for up to 8 days. Bromocriptine had no effect on the growth rate or prolactin secretion of the 235-1 clone but inhibited prolactin release from anterior pituitary cells by over 73% in control studies.We conclude that the 235-1 clone does not express dopamine receptors and that the presence of dopamine receptors is obligatory for the typical inhibitory effects of bromocriptine on prolactin release and pituitary cell growth.     

Oxytocin action at the lactotroph is required for prolactin surges in cervically stimulated ovariectomized rats

Cervical stimulation induces two daily rhythmic prolactin surges, nocturnal and diurnal, which persist for several days. We have shown that a bolus injection of oxytocin initiates a similar prolactin rhythm, which persists despite low levels of oxytocin after injection. This suggests that oxytocin may trigger the cervical stimulation-induced rhythmic prolactin surges. To investigate this hypothesis, we infused an oxytocin antagonist that does not cross the blood-brain barrier for 24 h before and after cervical stimulation and measured serum prolactin. We also measured dopaminergic neuronal activity because mathematical modeling predicted that this activity would be low in the presence of the oxytocin antagonist. We thus tested this hypothesis by measuring dopaminergic neuronal activity in the tuberoinfundibular, periventricular hypophyseal, and tuberohypophyseal dopaminergic neurons. Infusion of oxytocin antagonist before cervical stimulation abolished prolactin surges, and infusion of oxytocin antagonist after cervical stimulation abolished the diurnal and significantly decreased the nocturnal surges of prolactin. The rhythmic prolactin surges returned after the clearance of the oxytocin antagonist. Hypothalamic dopaminergic activity was elevated in antiphase with prolactin surges, and the antiphase elevation was abolished by the oxytocin antagonist in the tuberoinfundibular and tuberohypophyseal dopaminergic neurons, consistent with the mathematical model. These findings suggest that oxytocin is a physiologically relevant prolactin-releasing factor. However, the cervical stimulation-induced prolactin surges are maintained even in the absence of oxytocin actions at the lactotroph, which strongly suggests the maintenance of prolactin surges are not dependent upon oxytocin actions at the pituitary gland.     

The effect of galanin on growth hormone-releasing factor and somatostatin release from median eminence fragments in vitro.

Galanin has been reported to stimulate secretion of GH in humans and rats. Thus, to investigate whether the effect of galanin on GH release is the result of either a stimulation of GH-releasing factor (GRF) and/or an inhibition of somatostatin (SRIF) release, we have evaluated the action of galanin on the release of SRIF and GRF from median eminence (ME) fragments in vitro. The MEs from adult male rats were incubated in Krebs-Ringer bicarbonate-glucose buffer, pH 7.4, at 37 degrees C, in an atmosphere of 95% O2, 5% CO2 with constant shaking for 30 min. Medium was discarded and replaced by medium containing various concentrations of galanin (10(-10)-10(-7) M). Galanin stimulated SRIF and GRF release in a dose-related manner. This effect was significant at concentrations varying from 10(-8) to 10(-7) M. To determine the mechanism by which galanin stimulated SRIF and GRF release, MEs were incubated with pimozide (dopaminergic blocker), phentolamine (alpha-adrenergic blocker) or naloxone (opioid blocker), at concentrations of 10(-6) M, and the effect of galanin was then evaluated. Phentolamine and naloxone did not alter the stimulatory effect of galanin, but when galanin was tested with pimozide, the galanin-induced release of SRIF and GRF was blocked. To determine whether the effect of galanin is mediated through D-1 and/or D-2 dopamine receptors, selective antagonists of D-1 (SCH 23390) and D-2 receptors (domperidone) were used (10(-7) M) in the presence of galanin (10(-7) M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of gonadotropin release and of ovarian development, by the administration of a gonadoliberin agonist and of dopamine antagonists, in female silver eel pretreated with estradiol

In freshwater or seawater female silver eel, the release of gonadotropin (GTH) accumulated in the pituitary under estradiol (E2) influence could be stimulated by a conjugated treatment with a mammalian gonadoliberin agonist (GnRH-A = des-Gly10, (D-Ala6)-LH-RH ethylamide) and a blocker of dopamine receptor (pimozide). Furthermore, despite the GTH release, no reduction or even a significant increase in pituitary GTH levels were noted, indicating a stimulation of GTH synthesis. In consequence of the endogenous GTH release, a stimulation of ovarian development was induced, as demonstrated by the gonadosomatic index and histological study. Similar results were obtained with a combined treatment with GnRH-A and an inhibitor of catecholamine synthesis (L-alpha-methyl-3,4-dihydroxyphenylalanine). In contrast, no effect was produced by GnRH-A, pimozide, or L-alpha-methyl-DOPA, given alone. The results suggest that a double neuroendocrine mechanism (a lack of GnRH production and a dopaminergic inhibition of GnRH action) is involved in the prepubertal blockage of eel gonadotropic function before the reproductive migration.     

Mechanism of action of dopamine on the in vitro release of gonadotropin-releasing hormone

Controversy exists on whether dopamine (DA) stimulates or inhibits GnRH secretion and whether its effects are mediated via alpha-adrenergic receptors or dopaminergic receptors. As a means to examine this conflict, we have utilized an in vitro superfusion system to study the effects of DA, norepinephrine (NE), phentolamine (alpha-antagonist), pimozide (DA antagonist), and two DA agonists (apomorphine and bromocryptine) on GnRH release from isolated mediobasal hypothalami from adult male rats. In this dynamic system, graded concentrations of both NE and DA (2.0 nM to 2.0 microM) led to a dose-dependent increase in GnRH output during the 10 min interval that followed each pulse dose of NE (P less than 0.02) or DA (P less than 0.05). The DA-induced GnRH release was reproducible, consistent, and significant over five successive pulses (20 microM) at 30-min intervals (P less than 0.02). Coinfusion of phentolamine (20 microM) prevented the DA (20 microM) induced release of GnRH (P less than 0.03), but pimozide (20 microM) had no significant effect on DA-induced GnRH release (P greater than 0.3). The two DA agonists, apomorphine and bromocryptine, at doses up to 2.0 microM and 200 nM, respectively, had no significant effect on GnRH release. To determine whether DA was causing a direct stimulation of alpha-adrenergic receptors or being enzymatically converted to NE which could then stimulate alpha-receptors to induce GnRH release, rats were injected with sodium diethyldithiocarbamate (DDC) (550 mg/kg BW) ip, 1 h before death. DDC blocks the enzymatic conversion of DA to NE, and this was reflected by a 37% decrease in hypothalamic NE efflux during the superfusion. However, pulses of DA, even in the presence of DDC, were associated with a marked dose-dependent increase in hypothalamic NE efflux, and DDC failed to prevent the subsequent stimulation of GnRH release. We conclude that the apparent DA-induced release of GnRH is most probably attributable to DA-induced release of hypothalamic NE which, in turn, acts through alpha-adrenergic receptors on peptidergic neurons to stimulate GnRH release.     

Comparative studies of prolactin secretion in estradiol-primed and normal male rats induced by ether stress, pimozide and TRH

The differences in plasma prolactin concentration between normal and estradiol-implanted male rats were compared after treatment with 3 different stimulating agents of prolactin secretion [ether anesthesia, pimozide (a "specific' dopaminergic receptor blocking agent) and TRH] using conscious, free-moving rats implanted with permanent intra-atrial cannulae. It has recently been shown that ether stress raises the circulating prolactin concentration by stimulating PRF secretion. The ether stress elevated prolactin concentration from 100 to 400 ng/ml in the estradiol-implanted rat and from 10 to 40 ng/ml in the normal male. Thus, the ether stress elevated the prolactin concentration 4 times over the basal level in both normal male and estradiol-implanted male rats, implying that the physiological role of the PRF is not changed by the estradiol implantation. A bolus injection of pimozide (1 mg/kg) elevated the plasma prolactin concentration in both the normal and estradiol-implanted male with an initial surge followed by descent to a maintained plateau level. This plateau level in the estradiol-primed rat was 600 ng/ml and in the nonprimed male rat, 50 ng/ml. The ratio of the plateau concentration over the basal level was 4 times for both groups, suggesting that the physiological role of the PIF in the estradiol-implanted rat is not different from that in the normal male rat. It is known that TRH not only stimulates TSH secretion but will stimulate prolactin secretion as well. A very large dose (0.6 mg/kg) of TRH elevated prolactin concentration 6-fold in the estradiol-implanted rat but stimulate little prolactin secretion in the normal male rat. Since ether exposure appears to stimulate prolactin secretion in both estradiol-primed and non-primed male rats through PRF secretion, while TRH was not able to stimulate a significant amount of prolactin secretion in the normal male rat, we concluded that TRH acts to stimulate prolactin secretion in estradiol-primed rats but through a different mechanism than that operating for PRF.     

Pineal removal or denervation: effects on hypothalamic PRF activity in the rat.

Medial basal hypothalamic (MBH) extracts from intact, blind-anosmic, blind-anosmic-pinealectomized or nervi conarii transected female rats stimulated the release of prolactin from anterior pituitary glands in vitro. Additionally, a lower tissue level of prolactin was measured in the pituitaries incubated with the extracts. These data indicate that the activity of a prolactin-releasing factor(s) (PRF) was being assayed in the MBH extracts. Additionally, it was observed that MBH extracts from blind-anosmic-pinealectomized or nervi conarii transected rats contained significantly higher levels of PRF activity than the extracts from the intact or blind-anosmic groups. The results support the concept that the pineal control of pituitary prolactin may involve hypothalamic PRF.     

Effect of methysergide, a blocker of serotonin receptors, on plasma prolactin levels in lactating and ovariectomized rats.

The effect of methysergide (MES, 2.5 mg/100 g body wt), a serotonin antagonist, on prolactin release has been studied in lactating and ovariectomized rats. MES caused significant increases in prolactin release in both animals. Studies in ovariectomized, hypophysectomized rats indicate that this effect is not due to a decrease in the peripheral metabolism of prolactin. In vitro incubations of anterior pituitary fragments with MES failed to demonstrate any increase in prolactin release, suggesting that MES does not act directly on the anterior pituitary. Parachlorophenylalanine (PCPA; 32 mg/100 g body wt) decreased brain serotonin levels in ovariectomized rats 5, 24, and 70 h after its administration, yet did not alter plasma prolactin levels. L-tryptophan (6.3 mg/100 g body wt) given 1 and 1 1/2 h prior to sacrifice increased brain serotonin levels, yet did not affect plasma prolactin levels. Neither PCPA nor L-tryptophan altered MES-induced prolactin release. In lactating rats, suckling caused marked increases in plasma prolactin levels, an effect completely abolished by the administration of MES to the mother rats 3 1/4 h prior to suckling. However, MES-induced prolactin release was not altered by prior treatment with MES, either in lactating or ovariectomized rats. Others have shown that suckling releases prolactin through an excitatory serotonergic mechanism. Therefore, the failure of suckling to release prolactin in MES-pretreated rats suggests that MES can block brain serotonin receptors. However, the ability of methysergide to release prolactin in rats with serotonin receptors presumably blocked, suggests that the serotonin receptor-blocking and the prolactin-releasing actions of MES are not related.     

Dopaminergic mechanisms involved in prolactin release after mifepristone and naloxone treatment during late pregnancy in the rat

BACKGROUND/AIMS: During late pregnancy, the antiprogesterone mifepristone facilitates prolactin release. This effect is enhanced by administration of the opioid antagonist naloxone, suggesting an inhibitory-neuromodulatory role of the opioid system. Since hypothalamic dopamine (DA) is the main regulator of prolactin release, in this study we explored the role of DA on prolactin release induced by mifepristone and naloxone treatment. METHODS/RESULTS: Rats on day 19 of pregnancy were used. Naloxone treatment did not modify the 3,4-dihydroxyphenylacetic acid/DA (DOPAC/DA) ratio or serum prolactin concentration in control rats. After mifepristone treatment, DA activity diminished significantly without modifying serum prolactin levels. Naloxone administration to antiprogesterone-treated rats did not change the DOPAC/DA ratio but increased serum prolactin. Tyrosine hydroxylase (TH) expression in medial basal hypothalamus (MBH) protein extracts was lowered by pretreatment with mifepristone, with no additional effect of naloxone. While mifepristone decreased the intensity of TH immunoreactivity in the arcuate and periventricular nuclei and in fibers of the median eminence, naloxone treatment had no further effect. CONCLUSIONS: (1) A reduction of tuberoinfundibular dopaminergic (TIDA) neuron activity is suggested by the fall of the DOPAC/DA ratio and the low expression of MBH TH; (2) this reduction facilitates prolactin secretion by naloxone, indicating that progesterone stimulates DA neurons to maintain low serum prolactin; (3) naloxone action seems to depend on a previous decrease of DA tone induced by mifepristone, without involve a direct effect on neuronal DA activity, and (4) endogenous opioids may inhibit prolactin secretion through a non-dopaminergic neuronal system that regulates prolactin secretion in which as yet undetermined prolactin-releasing factors may participate.     

Responses to prolactin secretagogues in oestrogen-treated rats suggest that the defect in prolactin regulation produced by oestrogen is at the level of the pituitary gland

Prolactin responses to pharmacological agents were used to characterize the defect in prolactin regulation which occurs after administration of high doses of oestrogen to rats. Animals with chronically implanted venous cannulae were injected with 2 mg oestradiol benzoate in oil and 2-3 days later prolactin concentrations were measured after injections of saline, thyrotrophin-releasing hormone (TRH), fenfluramine, apomorphine and butaclamol. The responses were compared with those in oil-injected animals. Hyperprolactinaemia in oestrogen-treated animals was unresponsive to apomorphine, but was even more sensitive to dopamine receptor blockade than controls. These results suggest that the lactotrophs in oestrogen-treated animals are already maximally suppressed by endogenous dopamine, though ineffectively. Although there was an increased prolactin response to TRH in oestrogen-treated animals, there was an impaired response to fenfluramine, indicating suppressed serotonergic prolactin-releasing factor mechanisms. Maximal endogenous dopaminergic activity and suppressed prolactin-releasing factor mechanisms are appropriate hypothalamic responses to hyperprolactinaemia. The operation of these responses in the earliest stages of the development of pituitary hyperplasia indicates that oestrogen induces a disturbance of prolactin regulation in the lactotroph, independent of hypothalamic control.     

Dopaminergic suppression of pancreatic somatostatin secretion

To characterize dopaminergic influences on pancreatic islet D cell function and its potential interaction with islet A and B cell function, the effect of dopamine (0.5-100 micro M) on immunoreactive somatostatin (IRS), insulin (IRI), and glucagon (IRG) release from rat islets incubated in vitro was studied. Dopamine significantly suppressed the release of IRS (P less than 0.001) and IRI (P less than 0.001) and augmented IRG release (P less than 0.001). Maximum suppression of IRS and IRI release was evident at 20 micro M dopamine with half-maximal suppression occurring at 0.5-1 micro M. Maximal stimulation of IRG release was observed at 100 micro M dopamine with a half-maximal response occurring at 5-10 micro M. Suppression of IRS secretion by dopamine (20 micro M) was completely reversed by the dopaminergic antagonists haloperidol (5 micro M) and pimozide (5 micro M) but was only partially reversed by the alpha adrenergic antagonist phentolamine (2 micro M), and was further suppressed by the beta adrenergic antagonist phentolamine (2 micro M). Suppression of IRI release by dopamine was completely reversed by propranolol, but was unaffected by haloperidol, pimozide, and phentolamine. There results indicate that dopamine directly affects pancreatic islet D cell function, and that islet B and D cells appear to be more sensitive to dopamine than are A cells. Dopamine suppresses IRS secretion predominantly through activation of dopaminergic receptors, whereas it suppresses IRI release through an alpha adrenergic mechanism and stimulates IRG release through a beta adrenergic mechanism.     

The influence of adrenergic, dopaminergic, cholinergic and serotoninergic drugs on plasma prolactin levels in ovariectomized, estrogen-treated rats.

Levels of plasma prolactin were estimated in ovariectomized, estrogen-treated rats following the systemic administration of several neural blocking and stimulating drugs. Phenoxybenzamine, an alpha-adrenergic blocker, at high doses, increased plasma prolactin. Phenotlamine, another alpha-adrenergic blocker, and propranolol, a beta-adrenergic blocker, also increased prolactin but the responses were small and transient. Clonidine, an alpha-adrenergic stimulating drug, elevated prolactin levels whereas the beta-adrenergic stimulator isoproterenol had no effect. Dopaminergic blockade by pimozide increased levels of prolactin while stimulation of dopamine receptors by apomorphine decreased prolactin release. Atropine (a muscarinic chilinergic blocker), arecoline (a muscarinic stimulator) and nicotine (a nicotinic cholinergic stimulating drug) did not affect basal prolactin levels. Mecamylamine (a nicotinic blocker) produced a small transient elevation in plasma prolactin. Methiothepin, an alleged serotoninergic blocker, markedly increased prolactin secretion, as did serotonin. The data suggested the involvement of several neurotransmitters in the control of basal secretion of prolactin.     

Antiestrogens are partial estrogen agonists for prolactin production in primary pituitary cultures

The antiestrogens Ly-117018 and tamoxifen increased prolactin production about 2-fold in primary cultures of male rat anterior pituitary cells. The dose-response relationship was biphasic; 10(-10) M Ly-117018 and 10(-7) M tamoxifen caused maximal stimulation, but higher concentrations caused no stimulation and completely antagonized the 5-fold stimulation caused by estrogen. The calmodulin antagonists, trifluoperazine, pimozide and W7 also prevented estrogen induction of prolactin production. Increasing concentrations of estradiol reversed inhibition by tamoxifen but not by pimozide. These results indicate that, in normal pituitary cells, estrogen antagonists may behave as partial agonists at low concentrations and as full antagonists at higher concentrations (tamoxifen, prolactin, calmodulin, 17 beta-estradiol).