Reduced Prolactin Release Research Articles

Slow dissociation of partial agonists from the D2 receptor is linked to reduced prolactin release

In this study we investigated the correlation between affinity, efficacy, peripheral receptor occupancy, and kinetic properties of D₂ dopamine receptor ligands with time-course evaluations of prolactin release in rat blood. We profiled typical and atypical antipsychotic antagonists at D₂ receptors, the partial agonist aripiprazole, and four novel partial agonist compounds with different properties. Clozapine and quetiapine revealed lower prolactin release and fast dissociation kinetics, linking fast dissociation and prolactin-sparing properties. Surprisingly, haloperidol, a highly prolactin-releasing antagonist, shared intermediate dissociation properties. Factors other than kinetic properties may thus contribute to prolactin-releasing properties of antagonists. Partial agonists sharing similar efficacies and receptor occupancies differed markedly in their ability to induce hyperprolactinaemia. Aripiprazole moderately released prolactin even at high receptor occupancies, with slow dissociation from D₂ receptors. Other compounds displaying low affinities and fast dissociations released prolactin substantially, although less than haloperidol. The effect augmented after repeated administrations. Compounds with high affinities and slow dissociation rates stimulated moderate prolactin release at high receptor occupancies, reaching a ceiling effect at 50-60% occupancy. Moreover, the effect developed tolerance. In conclusion, we investigated the affinity and kinetic properties of D₂ partial agonists associated with their ability to induce prolactin release in blood. We propose that for D₂ partial agonists, at comparable intrinsic activities and peripheral occupancies, the prolactin-releasing properties are linked to their kinetic rate properties. Differently from D₂ antagonists, partial agonists display slow dissociation and high affinity associated with a low prolactin release profile.

Impaired CRH and Urocortin Expression and Function in Eutopic Endometrium of Women with Endometriosis

Women with endometriosis have altered endometrial function. CRH and urocortin (Ucn) are neuropeptides produced by human endometrium and modulate endometrial decidualization. To evaluate endometrial mRNA expression of CRH and Ucn, their role in in vitro decidualization of cultured human endometrial stromal cells (HESCs) in patients with endometriosis, and the role of CRH receptors (CHR-Rs). Obstetrics and Gynecology, University of Siena. Endometrial specimens were obtained from patients with and without endometriosis. Endometrial biopsy obtained at both phases of menstrual cycle. In vitro decidualization of HESCs collected from endometriosis or control was done in the presence of CRH, Ucn, or CRH receptor type 1 (CRH-R1, antalarmin) or type 2 (CRH-R2, astressin 2b) antagonists. Endometrial mRNA expression of CRH and Ucn during endometrial cycle; prolactin, CRH-R1, and CRH-R2 mRNA expression during in vitro decidualization. In healthy women CRH and Ucn expression were significantly higher (P < 0.05) in secretory than in proliferative phase; no differences were observed in endometriotic women. During in vitro decidualization, prolactin mRNA expression and release in endometriosis was lower than in control (P < 0.001). CRH and Ucn were able to significantly increase (P < 0.01) prolactin release only in control group; moreover, in this group antalarmin reduced prolactin release (P < 0.01). CRH-R1 mRNA expression increased during in vitro decidualization of HESCs in control (P < 0.01) but not in endometriosis. Women with endometriosis show an impaired endometrial expression of CRH and Ucn mRNA, and these neuropeptides are no more active in modulating the in vitro decidualization of HESCs, associated with a reduced expression of CRH-R1 mRNA.

Dependence of Electrical Activity and Calcium Influx-Controlled Prolactin Release on Adenylyl Cyclase Signaling Pathway in Pituitary Lactotrophs

Pituitary lactotrophs in vitro fire extracellular Ca2+-dependent action potentials spontaneously through still unidentified pacemaking channels, and the associated voltage-gated Ca2+influx (VGCI) is sufficient to maintain basal prolactin (PRL) secretion high and steady. Numerous plasma membrane channels have been characterized in these cells, but the mechanism underlying their pacemaking activity is still not known. Here we studied the relevance of cyclic nucleotide signaling pathways in control of pacemaking, VGCI, and PRL release. In mixed anterior pituitary cells, both VGCI-inhibitable and -insensitive adenylyl cyclase (AC) subtypes contributed to the basal cAMP production, and soluble guanylyl cyclase was exclusively responsible for basal cGMP production. Inhibition of basal AC activity, but not soluble guanylyl cyclase activity, reduced PRL release. In contrast, forskolin stimulated cAMP and cGMP production as well as pacemaking, VGCI, and PRL secretion. Elevation in cAMP and cGMP levels by inhibition of phosphodiesterase activity was also accompanied with increased PRL release. The AC inhibitors attenuated forskolin-stimulated cyclic nucleotide production, VGCI, and PRL release. The cell-permeable 8-bromo-cAMP stimulated firing of action potentials and PRL release and rescued hormone secretion in cells with inhibited ACs in an extracellular Ca2+-dependent manner, whereas 8-bromo-cGMP and 8-(4-chlorophenylthio)-2'-O-methyl-cAMP were ineffective. Protein kinase A inhibitors did not stop spontaneous and forskolin-stimulated pacemaking, VGCI, and PRL release. These results indicate that cAMP facilitates pacemaking, VGCI, and PRL release in lactotrophs predominantly in a protein kinase A- and Epac cAMP receptor-independent manner.

Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release

Dopamine D2 receptor antagonists induce hyperprolactinemia depending on the extent of D2 receptor blockade. We compared the effects of the new antipsychotic agents SSR181507 ((3-exo)-8-benzoyl- N-[[(2 s)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride), bifeprunox (DU127090: 1-(2-Oxo-benzoxazolin-7-yl)-4-(3-biphenyl)methylpiperazinemesylate) and SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine) with those of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy)-3,4-dihydro-2(1 H)-quinolinone), clozapine and haloperidol, on functional measures of dopamine D2 receptor activity in vitro and in vivo: [ 35S]-GTPγS binding to membranes from Sf9 insect cells expressing human dopamine D2 Long ( hD2 L) receptors, and serum prolactin levels in the rat. All compounds antagonized apomorphine-induced G protein activation at dopamine hD2 L receptors. Antagonist potencies of aripiprazole, bifeprunox and SLV313 were similar to haloperidol (p K b = 9.12), whereas SSR181507 (8.16) and clozapine (7.35) were less potent. Haloperidol, SLV313 and clozapine were silent antagonists but SSR181507, bifeprunox and aripiprazole stimulated [ 35S]-GTPγS binding by 17.5%, 26.3% and 25.6%, respectively, relative to 100 μM apomorphine ( E max = 100%). pEC 50s were: SSR181507, 8.08; bifeprunox, 8.97; aripiprazole, 8.56. These effects were antagonized by raclopride. Following oral administration in vivo, the drugs increased prolactin release to different extents. SLV313 and haloperidol potently (ED 50 0.12 and 0.22 mg/kg p.o., respectively) stimulated prolactin release up to 86 and 83 ng/ml. Aripiprazole potently (ED 50 0.66 mg/kg p.o.) but partially (32 ng/ml) induced prolactin release. SSR181507 (ED 50 4.9 mg/kg p.o.) also partially (23 ng/ml) enhanced prolactin release. Bifeprunox only weakly increased prolactin at high doses (13 ng/ml at 40 mg/kg) and clozapine only affected prolactin at the highest dose tested (41 ng/ml at 40 mg/kg). Prolactin levels of the corresponding vehicle-treated animals were < 4.3 ng/ml. These data show that (1) SSR181507, aripiprazole and bifeprunox, but not SLV313, are partial agonists at dopamine hD2 L receptors in vitro; (2) SSR181507, bifeprunox and aripiprazole exhibit reduced prolactin release in vivo compared with drugs that are neutral antagonists at dopamine D2 receptors.

Cortisol rapidly suppresses intracellular calcium and voltage-gated calcium channel activity in prolactin cells of the tilapia (Oreochromis mossambicus).

Cortisol was previously shown to rapidly (10-20 min) reduce the release of prolactin (PRL) from pituitary glands of tilapia (Oreochromis mossambicus). This inhibition of PRL release by cortisol is accompanied by rapid reductions in (45)Ca(2+) and cAMP accumulation. Cortisol's early actions occur through a protein synthesis-independent pathway and are mimicked by a membrane-impermeable analog. The signaling pathway that mediates rapid, nongenomic membrane effects of glucocorticoids is poorly understood. Using the advantageous characteristics of the teleost pituitary gland from which a nearly pure population of PRL cells can be isolated and incubated in defined medium, we examined whether cortisol rapidly reduces intracellular free calcium (Ca(i)(2+)) and suppresses L-type voltage-gated ion channel activity in events that lead to reduced PRL release. Microspectrofluorometry, used in combination with the Ca(2+)-sensitive dye fura 2 revealed that cortisol reversibly reduces basal and hyposmotically induced Ca(i)(2+) within seconds (P < 0.001) in dispersed pituitary cells. Somatostatin, a peptide known to inhibit PRL release through a membrane receptor-coupled mechanism, similarly reduces Ca(i)(2+). Under depolarizing [K(+)], the L-type calcium channel agonist BAY K 8644, a factor known to delay the closing of L-type Ca(2+) channels, stimulates PRL release in a concentration-dependent fashion (P < 0.01). Cortisol (and somatostatin) blocks BAY K 8644-induced PRL release (P < 0.01; 30 min), well within the time course over which its actions occur, independent of protein synthesis and at the level of the plasma membrane. Results indicate that cortisol inhibits tilapia PRL release through rapid reductions in Ca(i)(2+) that likely involve an attenuation of Ca(2+) entry through L-type voltage-gated Ca(2+) channels. These results provide further evidence that glucocorticoids rapidly modulate hormone secretion via a membrane-associated mechanism similar to that observed with the fast effects of peptides and neurotransmitters.

Heme oxygenase in the rat anterior pituitary: immunohistochemical localization and possible role in gonadotropin and prolactin secretion.

The objectives of this study were to determine if heme oxygenase (HO), which catalyzes the degradation of heme and the formation of carbon monoxide (CO), is localized in the rat anterior pituitary and, if so, to determine if hemin (a substrate for HO) or chromium mesoporphyrin (CrMP) (an inhibitor of HO), alter pituitary gonadotropin and prolactin secretion. For localization of HO, sections of anterior pituitaries obtained from mature Holtzman Sprague-Dawley rats in different stages of the estrous cycle were immunostained for two of the HO isoforms, HO-1 and HO-2. The immunostaining for the inducible HO isoform (HO-1) was limited to discrete populations of pituitary cells, whereas the constitutive isoform (HO-2) had a more widespread distribution. The afternoon surge of leutinizing hormone (LH) in the plasma of ovariectomized, estradiol-treated rats was advanced by 2 hr after 7 days of treatment with CrMP (4 micro M/kg), and this effect was reversed when hemin (30 micro M/kg) was co-administered with CrMP. The afternoon follicle-stimulating hormone (FSH) surge was not affected by either treatment. In contrast, the afternoon prolactin (PRL) surge was completely blocked or delayed by CrMP treatment, and this effect was not reversed by hemin. In vitro perifusion of pituitary explants with CrMP also significantly reduced PRL release compared with secretion from untreated explants. In vitro gonadotropin-releasing hormone (GnRH)-stimulated FSH secretion was significantly increased from pituitary explants of ovariectomized, estradiol-treated rats treated in vivo with hemin but was unaffected by CrMP treatment, whereas GnRH-stimulated LH release was not affected by hemin but was increased by CrMP treatment. In conclusion, this study demonstrates that HO exists in the rat anterior pituitary gland, and that a substrate and an inhibitor of this enzyme alter the secretion of gonadotropins and PRL.

Cortisol suppresses prolactin release through a non-genomic mechanism involving interactions with the plasma membrane

In the classical theory of steroid hormone action, steroids diffuse through the membrane and alter transcription of specific genes resulting in synthesis of proteins important for modulating cell function. Most often, steroids work solely through the genome to exert their physiological actions in a process that normally takes hours or days to occur. In tilapia (Oreochromis mossambicus), cortisol inhibits prolactin (PRL) release within 10–20 min in vitro. This action is accompanied by similarly rapid reductions in cellular Ca2+ and cAMP levels, second messengers known to transduce the membrane effects of peptide hormones. We further examined whether cortisol might inhibit PRL release through a non-genomic, membrane-associated mechanism using the protein synthesis inhibitor, cycloheximide, and a membrane impermeant form of cortisol, cortisol-21 hemisuccinate BSA (HEF/BSA). Cycloheximide (2 and 10 μg/ml) was ineffective in overcoming PRL release induced by hyposmotic medium or that inhibited by cortisol over 4 h static incubations. These dosages reduced protein synthesis as measured by amino acid incorporation in pituitaries by 75 and 99%, respectively. During 4-h incubation, HEF/BSA and HEF significantly reduced PRL release in a dose-dependent fashion. These studies suggest that cortisol inhibits PRL release through a plasma membrane-associated, protein-synthesis independent (non-genomic) pathway.

Stimulating Effect of Glycoprotein Hormone Free α‐Subunit and Daily Gonadotropin Releasing Hormone Treatment on Prolactin Release from 50‐Day Ovine Foetal Pituitary Explants

AbstractThe aim of our study was to determine whether free α of glycoprotein hormones (free α) plays a role in lactotroph function during early pituitary development in the sheep foetus. Detection and quantification of free α, luteinzing hormone β‐subunit (LHβ) and prolactin immunolabelling were determined by immunocytochemistry at days 32, 37, 42, 50 and 63 of gestation. Free α‐ and LHβ‐containing cells were first detected in the ovine foetal pituitary gland on day 37 of gestation, while prolactin‐containing cells were first identified on day 42. Analysis of serial sections suggested that free α immunoreactive cells were also LHβ‐positive, indicating that free α was mainly synthesized by gonadotrophs. In early foetal stages, free α occurred in the antero‐medio ventral region of the pituitary gland, whereas prolactin‐containing cells were more dorsally and more caudally localized. The free α‐, LHβ‐ and prolactin‐immunostained area increased markedly between days 50 and 63 of gestation. To evaluate a possible functional relationship between gonadotrophs and lactotrophs, the effects of free α or gonadotropin releasing hormone (GnRH) on prolactin release were assayed. Chronic treatment of pituitary explants from male and female 42‐day‐old ovine foetuses for 8 days with 10−9 or 10−7 M ovine free α did not affect prolactin release. By contrast, free α administration on pituitary explants from male and female 50‐day‐old foetuses resulted in enhanced prolactin release. At this age, a daily (2 h per day) treatment with 10−8 M GnRH had similar stimulatory effect to free α whereas a ‘first day’ treatment (24 h on the first day) reduced prolactin release throughout the culture in males and had no effect in females. These results indicate that, despite early detection of free α at day 37 in the ovine foetal pituitary, its stimulatory effect on prolactin release occurs from day 50 of gestation, corresponding to the first period of lactotroph development in vivo. A daily treatment with GnRH mimics the effect of free α on prolactin release.

Stimulating effect of glycoprotein hormone free alpha-subunit and daily gonadotropin releasing hormone treatment on prolactin release from 50-day ovine foetal pituitary explants.

The aim of our study was to determine whether free alpha of glycoprotein hormones (free alpha) plays a role in lactotroph function during early pituitary development in the sheep foetus. Detection and quantification of free alpha, luteinzing hormone beta-subunit (LHbeta) and prolactin immunolabelling were determined by immunocytochemistry at days 32, 37, 42, 50 and 63 of gestation. Free alpha- and LHbeta-containing cells were first detected in the ovine foetal pituitary gland on day 37 of gestation, while prolactin-containing cells were first identified on day 42. Analysis of serial sections suggested that free alpha immunoreactive cells were also LHbeta-positive, indicating that free alpha was mainly synthesized by gonadotrophs. In early foetal stages, free alpha occurred in the antero-medio ventral region of the pituitary gland, whereas prolactin-containing cells were more dorsally and more caudally localized. The free alpha-, LHbeta- and prolactin-immunostained area increased markedly between days 50 and 63 of gestation. To evaluate a possible functional relationship between gonadotrophs and lactotrophs, the effects of free alpha or gonadotropin releasing hormone (GnRH) on prolactin release were assayed. Chronic treatment of pituitary explants from male and female 42-day-old ovine foetuses for 8 days with 10-9 or 10-7 M ovine free alpha did not affect prolactin release. By contrast, free alpha administration on pituitary explants from male and female 50-day-old foetuses resulted in enhanced prolactin release. At this age, a daily (2 h per day) treatment with 10-8 M GnRH had similar stimulatory effect to free alpha whereas a 'first day' treatment (24 h on the first day) reduced prolactin release throughout the culture in males and had no effect in females. These results indicate that, despite early detection of free alpha at day 37 in the ovine foetal pituitary, its stimulatory effect on prolactin release occurs from day 50 of gestation, corresponding to the first period of lactotroph development in vivo. A daily treatment with GnRH mimics the effect of free alpha on prolactin release.

Role of the Na +-Ca 2+ and Na +-H + antiporters in prolactin release from anterior pituitary cells in primary culture

2′,4′-dimethylbenzamilamiloride (DMB), a somewhat selective inhibitor of the Na +-Ca 2+ exchanger, in concentrations of 10, 30 and 100 μM did not produce any significant effect on baseline prolactin release from anterior pituitary cells in primary culture. When prolactin secretion was stimulated by the inhibitor of the Na +-K +-ATPase, ouabain, that activates the Na +-Ca 2+ exchanger as a Ca 2+-influx pathway, DMB was able to produce inhibition of prolactin secretion. 5-( N,N-hexamethylene) amiloride (HMA), another amiloride analog which specifically inhibits the Na +-H + antiporter and has no inhibitory activity on the Na +-Ca 2+ exchanger, at the concentrations of 0.1, 1 and 10 μM, did not affect basal prolactin release whereas it significantly reduced prolactin release stimulated by thyrotropin releasing hormone (TRH) (1 μM). These results suggest that the Na +-Ca 2+ antiporter is involved in the process of prolactin release elicited by the inhibition of the Na +-K +-ATPase whereas the Na +-H + antiporter is involved in the prolactin secretion elicited by TRH.

Reduced prolactin release during immobilization stress in thyrotoxic rats: role of the central serotoninergic system.

Adult Wistar male rats in a thyrotoxic state T4 increases rats) induced by administration of T4 (350 micrograms/kg/day, i.p. for 7 days) as well as their euthyroid controls were submitted to immobilization stress during forty minutes. Prolactin (PRL) secretion during stress was significantly lower in T4 increases rats as compared to control animals. Treatment with MK 212, a serotoninergic agonist, entirely reverts this situation. The effect of MK 212 seems to be due to its interaction with 5-HT2 receptors since it is blocked by LY 53857, a selective 5-HT2 antagonist. Furthermore, the blockade of 5-HT2 receptors by LY 53857, a selective 5-HT2 antagonist, significantly diminishes prolactin (PRL) response to stress in euthyroid rats but has no effect in T4 increases animals. It is suggested that an increased concentration of thyroid hormone in plasma disrupts an endogenous serotoninergic brain input necessary to trigger stress-induced PRL rise.

Role of nitric oxide in control of prolactin release by the adenohypophysis.

Nitric oxide synthase-containing cells were visualized in the anterior pituitary gland by immunocytochemistry. Consequently, we began an evaluation of the possible role of NO in the control of anterior pituitary function. Prolactin is normally under inhibitory hypothalamic control, and in vitro the gland secretes large quantities of the hormone. When hemipituitaries were incubated for 30 min in the presence of sodium nitroprusside, a releaser of NO, prolactin release was inhibited. This suppression was completely blocked by the scavenger of NO, hemoglobin. Analogs of arginine, such as NG-monomethyl-L-arginine (NMMA, where NG is the terminal guanidino nitrogen) and nitroarginine methyl ester, inhibit NO synthase. Incubation of hemipituitaries with either of these compounds significantly increased prolactin release. Since in other tissues most of the actions of NO are mediated by activation of soluble guanylate cyclase with the formation of cyclic GMP, we evaluated the effects of cyclic GMP on prolactin release. Cyclic GMP (10 mM) produced an approximately 40% reduction in prolactin release. Prolactin release in vivo and in vitro can be stimulated by several peptides, which include vasoactive intestinal polypeptide and substance P. Consequently, we evaluated the possible role of NO in these stimulations by incubating the glands in the presence of either of these peptides alone or in combination with NMMA. In the case of vasoactive intestinal polypeptide, the significant stimulation of prolactin release was augmented by NMMA to give an additive effect. In the case of substance P, there was a smaller but significant release of prolactin that was not significantly augmented by NMMA. We conclude that NO has little effect on the stimulatory action of these two peptides on prolactin release. Dopamine (0.1 microM), an inhibitor of prolactin release, reduced prolactin release, and this inhibitory action was significantly blocked by either hemoglobin (20 micrograms/ml) or NMMA and was completely blocked by 1 mM nitroarginine methyl ester. Atrial natriuretic factor at 1 microM also reduced prolactin release, and its action was completely blocked by NMMA. In contrast to these results with prolactin, luteinizing hormone (LH) was measured in the same medium in which the effect of nitroprusside was tested on prolactin release, there was no effect of nitroprusside, hemoglobin, or the combination of nitroprusside and hemoglobin on luteinizing hormone release. Therefore, in contrast to its inhibitory action on prolactin release NO had no effect on luteinizing hormone release. Immunocytochemical studies by others have shown that NO synthase is present in the folliculostellate cells and also the gonadotrophs of the pituitary gland. We conclude that NO produced by either of these cell types may diffuse to the lactotropes, where it can inhibit prolactin release. NO appears to play little role in the prolactin-releasing action of vasoactive intestinal polypeptide and substance P, but mediates the prolactin-inhibiting activity of dopamine and atrial natriuretic factor.

Effect of ergovaline, lolinc, and dopamine antagonists on rat pituitary cell prolactin release in vitro

Summary Cultured rat pituitary cells were studied to: determine the effects of ergovaline and loline on in vitro prolactin release; delineate the agonistic activity of these alkaloids at the D2 dopamine receptor, using 2 selective D2 dopamine receptor antagonists; and compare the efficacy of 2 dopamine receptor antagonists in reversing effects of the treatments on in vitro prolactin secretion. Ergovaline reduced in vitro prolactin release by at least 40% (P &lt; 0.05) at concentrations of 10−4, 10−6, and 10−8M However, loline reduced (P &lt; 0.05) prolactin release only at the highest concentration, 10−4 M. Two standard dopamine agonists, dopamine and α-ergocryptine, were used to verify that the inhibitory control mechanisms of in vitro prolactin release were intact. Both compounds reduced prolactin release by at least 40% for concentrations of 10−4, 10−6, or 10−8M. Selective D2 dopamine receptor antagonists (10−6M), domperidone and sulpiride, reversed (P &lt; 0.05) the effect of loline on in vitro prolactin release. However, only domperidone (10−6M) was able to reverse (P &lt; 0.05) the effect of ergovaline and only at the lowest ergovaline concentration (10−8M). Domperidone was more effective (P &lt; 0.05) in reversing the prolactinsuppressing effect of α-ergocryptine than was sulpiride. The dose-response curve for domperidone (cubic fit, P &lt; 0.0001) indicated a threshold concentration (10−7M) for reversal of a-ergocryptine's (10−8M) effect on prolactin release. However, at similar concentration of sulpiride (quadratic fit, P &lt; 0.007), a threshold level was not obtained. These data indicate that ergovaline and loline may act as D2 dopamine receptor agonists. Additionally, domperidone seems to be a more potent drug for reversal of the alkaloids’ hypoprolactinemic effect in vitro than does sulpiride.

The Regulation of Prolactin Cells in the Rainbow Trout ( Oncorhynchus mykiss) : 2. Somatostatin

The regulation of rainbow trout prolactin (PRL) cells has been investigated. (PRL) cell activity was assessed using acid gel electrophoresis to measure PRL release in vitro and image analysis to measure PRL cell nuclear area, an index of synthetic activity. Somatostafin (SRIF) reduced PRL release during a 3-hr incubation, but not during 18 hr unless the protease inhibitor, bacitracin, was included in the medium. Synthesis during 18 hr was inhibited by SRIF, an effect also enhanced by bacitracin. The effect of SRIF appears to be relatively short-lived, presumably due to proteolytic degradation. The SRIF antagonist cyclo[7-aminohepatanoyl-Phe-D-Trp-Lys-Thr(BZL)] blocked the inhibitory effect of SRIF. A 48-hr pretreatment with 17β-oestradiol to stimulate PRL cell activity did not prevent the inhibitory effects of SRIF, rather the response was enhanced. This evidence further supports a role for SRIF in regulation of rainbow trout PRL secretion.

Octopamine and Phenylethylamine Inhibit Prolactin Secretion both In Vivo and In Vitro

Trace amines are a group of biogenic amines that are present in neural tissue in concentrations ranging from 0.1 to 100 ng/g. In the present work, we examined the action of two trace amines, octopamine and phenylethylamine, which are found in the hypothalamus, on pituitary hormone secretion in different experimental situations in vivo and in dispersed anterior pituitary cells. Both octopamine and phenylethylamine decreased high prolactin levels due to swimming or immobilization stress without affecting other adenohypophysial hormones. With regard to the hypoprolactinemic potencies in the immobilization stress model, it was observed that p-tyramine, another trace amine, was as potent as octopamine. Phenylethylamine was the least effective. To evaluate the site of action of the effect described, the three trace amines were tested in dispersed anterior pituitary cell cultures in vitro. Tyramine and octopamine reduced prolactin secretion in a concentration-dependent manner, at concentrations of 10(-8) to 10(-5) M, whereas the hypoprolactinemic effect observed for phenylethylamine was very weak. In pharmacologic experiments, neither octopamine nor phenylethylamine reduced prolactin release when dopaminergic receptors were blocked. This could mean that their hypoprolactinemic action was mediated through the release of dopamine, or it could be a direct action at a dopaminergic receptor. This is the first description of a specific endocrine action both in vivo and in vitro for octopamine and phenylethylamine. Further studies are needed to ascertain the physiologic or pathologic implication of these findings.

A selective role for brain histamine in prolactin release induced by opiates

We studied the effects of histamine (HA) antagonists on the facilitatory action of morphine (M) and beta-endorphin (beta E) on prolactin (PRL) release and the effect of alpha-fluoromethylhistidine (alpha-FMH, inhibitor of HA synthesis) on beta E-induced PRL secretion. Male rats were injected intracerebroventricularly (i.c.v.) with mepyramine (MEP, H1-antagonist, 0.8 mumol/rat) or ranitidine (RAN, H2-antagonist, 0.4 mumol/rat) 10 min before M (6 mg/kg, intracarotid, i.a.) or beta E (0.25 micrograms/rat, i.c.v.). alpha-FMH (200 micrograms/rat, i.c.v.) was administered 3 h before beta E. Plasma PRL levels were measured at various times before and after drug treatment. RAN but not MEP significantly reduced PRL release induced by M whereas neither HA-antagonists nor alpha-FMH modified beta E-induced PRL release. The results obtained show that brain HA contributes through activation of H2-receptors to the PRL facilitatory action of M but not of beta E.

Inhibition of puerperal lactation by metergoline: interactions with methylergobasine maleate.

Metergoline, a prolactin (PRL) lowering drug, is used in the puerperal period to inhibit lactation. Methylergobasine maleate (MEM), widely employed in the puerperium to promote uterine contractions, has also been reported to decrease PRL release and to reduce lactation. To evaluate the possible interactions of the two drugs, groups of 6-11 puerperae each received no treatment, metergoline alone (8 or 12 mg/day for 5 days), MEM alone (0.2 mg i.v. at delivery followed by 0.5 mg/day p.o. for 5 days) and metergoline plus MEM. Metergoline fully prevented lactation and significantly reduced PRL release, the higher dose inducing effects faster. MEM was without effect on PRL release and lactation, and did not modify the effect of metergoline.

Inhibitton of prolactin release by stimulation of presynaptic serotonin autoreceptors

The effects of 5-methoxy-N, N-dimethyltryptamine (5-MeODMT), a serotonin agonist with a preferential action on presynaptic autoreceptors, on prolactin release in male rats was determined. Basal serum prolactin levels were not altered after administration of 1.0, 2.0, 5.0, 10.0 or 20.0 mg/kg of 5-MeODMT. Pretreatment with 5-MeODMT reduced prolactin release by agents that depend on serotonergic neurotransmission for part of their prolactin release stimulation. Prolactin release in response to L-5-hydroxytryptophan (5-HTP) or morphine was significantly reduced by pretreatment of the rats with 5-MeODMT. The results of this experiment indicate that 5-MeODMT act as a presynaptic serotonin autoreceptor stimulant and not as a postsynaptic serotonin agonist on the neuronal systems that control prolactin release.

Effect of GABA agonists and modulators on prolactin release

Administration of GABA agonists has been found both to stimulate and inhibit prolactin secretion in vivo. These independent actions represent a stimulatory effect after intracerebroventricular injection mediated by an action within the CNS and an inhibitory response resulting from a direct action of GABA on the pituitary cell membrane to reduce prolactin release. Thus the response to exogenously administered GABA or its agonists depends on the route of injection. In this study amino oxyacetic acid and isonicotinic acid hydrazide were given to increase or decrease respectively the concentration of endogenous GABA. Benzodiazepine was used to enhance the affinity of the receptor for endogenous GABA. Unlike the agonists used previously these drugs enter the CNS after systemic administration and can thus produce two opposing effects. The results indicated that increased blood and brain GABA content or receptor affinity was associated with reduced prolactin release. These effects however were more significant when basal prolactin secretion was stimulated by estrogen or haloperidol.

Regulation of prolactin release by endogenous opiates

ENDORPHINS, the endogenous peptides recently isolated and identified in brain have been implicated in regulation of pain1–4. But their wide distribution throughout the brain5–7 and their profound behavioural effects after central administration8 suggest an involvement in other central nervous system processes. Immunohistochemical identification of these endorphins (refs 9, 10 and F. Bloom, personal communication) in hypothalamic neurones indicated that neuroendocrine effects are probable. Morphine was previously reported to block ovulation, while more recently, morphine11 and endorphins12–14 were observed to stimulate release of prolactin and growth hormone. Yet, these observations have not established a direct, tonic participation of endorphins in hypothalamic and anterior pituitary function. The absence of any direct action of opiate antagonists has been taken as an argument against any tonic role of endorphins. Recent reports indicate, however, that opiate antagonists do modify on-going central processes. For example, naloxone and naltrexone lower pain threshold in appropriate conditions in man and experimental animals15–18. Using naltrexone as a tool to block opiate receptor function, we have explored whether endorphins are tonically involved as a putative neurotransmitter in the regulation of prolactin release. The results presented here demonstrate a new instance where an opiate antagonist modifies normal function. The data agree with a preliminary report indicating that naloxone reduced prolactin release in immature female rats19.