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.     

Effects of acute and chronic trazodone administration on serum prolactin levels in adult female rats

Trazodone was tested for its ability to elevate serum prolactin levels in mature female rats. When the drug was administered acutely to female rats at doses up to 80 mg/kg ip, it induced a clear rise in serum prolactin levels, with a minimum effective dose of 20 mg/kg; blood trazodone levels at these doses were between 1.6–2.4 μg/ml. However, trazodone could not be considered to be a potent stimulator of prolactin secretion, since the injection of haloperidol at 2 mg/kg elevated serum prolactin to values twice those seen in animals receiving the 80 mg/kg dose of trazodone. When trazodone was administered chronically in the diet for two or four weeks, at an average daily dose of 80 mg/kg, serum trazodone levels were found to be 100–200 ng/ml when measured at each stage of the estrous cycle. Serum prolactin levels in trazodone-treated animals, however, did $\text{not}$ differ from those in control rats. Moreover, drug-treated animals showed normal proestrus surges in serum prolactin. The results of these studies thus indicate that acutely, at very high doses, trazodone probably can stimulate prolactin secretion modestly in female rats. However, when consumed chronically at 80 mg/kg/day, the drug has no effects on serum prolactin levels. Therefore, if trazodone stimulates prolactin secretion by altering neurotransmission across dopamine and/or serotonin synapses in brain, it is probably not potent in these actions, at least as concerns those dopamine and serotonin neurons that influence the secretion of prolactin.     

硬膜外腔单次注射吗啡联合地佐辛静脉用于剖宫产术后镇痛的疗效及对患者血清5-羟色胺、泌乳素水平的影响

目的:探讨硬膜外腔单次注射吗啡联合地佐辛静脉用于剖宫产术后镇痛的疗效及对患者血清5-羟色胺、泌乳素水平的影响。方法:选择2016年1月至2018年11月择期进行剖宫产的产妇80例,按照随机数字法将其分为观察组和对照组,每组各40例。对照组采用硬膜外腔单次注射吗啡自控镇痛,观察组采用硬膜外腔单次注射吗啡联合地佐辛静脉自控镇痛。采用视觉模拟评分法(VAS)评估两组产妇术后镇痛效果,酶联免疫法及化学发光法分别测定产妇术前、术后6 h、12 h、24 h和48 h血清5-羟色胺水平及泌乳素水平,并观察两组产妇术后不良反应的发生情况。结果:两组产妇患者术后VAS评分随着时间延长逐渐降低,观察组术后第6 h、12 h、24 h以及48 h的VAS评分均显著低于对照组(P0.05);两组产妇术后血清5-羟色胺水平均较术前明显降低(P0.05),而血清泌乳素均较术前显著升高(P0.05),且观察组术后第6 h、12 h、24 h以及48 h血清5-羟色胺水平均显著低于对照组(P0.05),而血清泌乳素浓度均明显高于对照组(P0.05)。两组产妇患者术后均未出现呼吸抑制,对照组恶心(Nausea)、呕吐、头晕、皮肤瘙痒的发生率明显低于对照组(P0.05)。结论:硬膜外腔单次注射吗啡联合地佐辛静脉用于剖宫产术后镇痛疗效及安全性均较硬膜外腔单次注射吗啡自控镇痛更好,产妇术后血清泌乳素及5-羟色胺浓度显著提高,对于产后抑郁的发病可能有一定的抑制作用,也有利于产妇术后恢复,尽早哺乳。     

Effect of serotonin depletion by p-chlorophenylalanine on serum prolactin levels in estrogen-treated ovariectomized rats: insights concerning the serotoninergic, dopaminergic and opioid systems.

The stimulatory effect of serotonin on prolactin secretion is well documented, and the administration of an inhibitor of serotonin synthesis (p-chlorophenylalanine - pCPA) has the expected inhibitory action on prolactin release in most experimental situations. However, there is evidence that in certain physiological or experimental conditions, activation of the serotoninergic system can also determine inhibition of prolactin secretion. The aim of the present study was to investigate the ability of estrogen to modify the effect of pCPA on prolactin secretion and to evaluate the participation of opioid and/or dopaminergic systems in regulating pCPA-induced prolactin secretion in estradiol-treated rats. We observed that pCPA administration (200 mg/kg/day, s.c., 2 days) to ovariectomized (OVX) female rats treated with estradiol benzoate (300 microg/week for 2 weeks, or 50 microg/week for 4 weeks, s.c.) causes a significant increase in serum prolactin, whereas no effect is observed in intact rats or in OVX rats without treatment. Bromocriptine administration completely reversed prolactin values previously increased by estradiol and by pCPA [OVX rats + estradiol = 86.50 ng/ml (68.90-175.02), OVX + estradiol + pCPA = 211.30 ng/ml (142.03-311.00), OVX + estradiol + pCPA + bromocriptine = 29.35 ng/ml (23.01 - 48.74), p<0.05. Naloxone administration partially reduced estrogen-induced high prolactin concentrations, but did not affect prolactin secretion stimulation determined by pCPA. Overall, the data from this report confirm the involvement of the dopaminergic system and, to a lesser degree, of endogenous opioids in prolactin secretion stimulation determined by estradiol. Furthermore, our results suggest that the stimulatory action of pCPA on prolactin secretion in estradiol-treated OVX rats is mediated by serotonin, which may also act indirectly on dopamine neurons.     

Quipazine-metoclopramide inhibition of CB-154-induced prolactin suppression in rats: neurotransmitter-metabolite correlations

The ability of quipazine and metoclopramide to protect rats from CB-154-induced suppression of serum prolactin concentrations was studied. These drugs affect whole brain concentrations of dopamine and serotonin, and their major metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. Serum prolactin concentrations have been correlated with the concentrations of the neurotransmitters and their respective metabolites. Differences in the metabolite/precursor ratios have been used to compare turnover rates of the neurotransmitters dopamine and serotonin. Increased turnover of dopamine and decreased turnover of serotonin correlate with elevated prolactin concentrations for quipazine and metoclopramide administered together. The combination of quipazine and metoclopramide protects rats against CB-154-induced prolactin suppression better than either of the drugs given alone. This study suggests that a quipazine-metoclopramide regimen may have therapeutic potential for combating ergotlike fescue and other similar toxicities observed in cattle grazing on endophyte-infected pasture grasses.     

Serum prolactin and brain and pituitary monoamine responses to chronic monoamine oxidase inhibition in the rat.

The acute administration of the monoamine oxidase inhibitor iproniazid to rats causes a highly significant suppression of serum prolactin levels at 2 h. At the same time there is a significant rise in the hypothalamic-median eminence concentrations of the biogenic monoamines dopamine, noradrenaline and serotonin. When iproniazid is administered daily to rats for 4 days and the animals are examined on the fifth day brain noradrenaline and serotonin levels are elevated similarly to those seen after acute administration but dopamine concentration is near normal while serum prolactin is significantly elevated. This study thus demonstrates that a quite specific and unexpected change occurs in the regulation of hypothalamic-median eminence dopamine when iproniazid is administered chronically and provides an explanation of previous observations in human subjects where raised serum prolactin levels are observed after chronic therapy with monoamine oxidase inhibitors.     

Effect of quipazine on rat plasma prolactin levels

Quipazine (2-(1-piperazinyl) quinoline maleate), a serotonin agonist which also has other effects on serotonin metabolism, in doses from 2.5 – 20 mg/kg, i.p., was found to markedly increase plasma prolactin levels in male rats. This increase was blocked by the serotonin antagonists methysergide and brom-lysergic acid diethylamide and potentiated by para-chlorophenylalanine, an inhibitor of serotonin synthesis. These findings suggest that the increase in plasma prolactin levels is due to the serotonin agonist properties of quipazine. Apomorphine and 2-Br-α-ergocryptine pretreatment blocked the effect on plasma prolactin of quipazine, while apomorphine given 15 min after quipazine brought about a rapid decline in the elevated plasma prolactin levels produced by quipazine.     

The effect of d-fenfluramine on anterior pituitary hormone release in the rat: in vivo and in vitro studies

Administration of d-fenfluramine, a serotonin-releasing drug, to male rats induced a dose-dependent increase in both serum prolactin and corticosterone concentrations. Serum growth hormone levels increased, but not significantly, at a dose of 1.25 mg/kg i.p. and decreased significantly at higher doses. When rats were pretreated with the serotonin uptake inhibitor fluoxetine (10 mg/kg i.p.) 30 min prior to injection of d-fenfluramine (5 mg/kg i.p.), the serum prolactin response to d-fenfluramine was partially inhibited, whereas the growth hormone response was not significantly modified. Fluoxetine pretreatment increased the serum corticosterone to the same level as did d-fenfluramine. d-Fenfluramine's effect on prolactin and growth hormone release was further tested in a hypothalamic-pituitary in vitro system. The addition of d-fenfluramine (5-500 ng/mL) for 30 min to rat hypothalami resulted in an enhancement of prolactin and growth hormone-releasing activities. These were expressed as the ability of the media in which the hypothalami had been incubated to stimulate prolactin and growth hormone release by cultured pituitary cells. The data suggest that the effect of d-fenfluramine on prolactin secretion is exerted through the hypothalamus and is probably mediated, at least partially, by a serotoninergic mechanism. The mechanism of d-fenfluramine's effect on corticosterone and growth hormone release needs further evaluation.     

Effects of naloxone on the secretion of prolactin and corticosterone induced by 5-hydroxytryptophan and a serotonergic agonist, mCPP

The effects of naloxone, an opiate “pure” receptor antagonist, on the release of prolactin and corticosterone in the rat were studied following the administration of the serotonin precursor 5-hydroxytryptophan or the serotonin receptor agonist (?) -$\text{m}$-chloropnehylpiperazine. Naloxone clearly antagonizes the release of prolactin induced by 5-hydroxytryptophan administered alone at a dosage of 50 mg/Kg/b.wt. or at dosage of 30 mg/Kg/b.wt. preceded 60 minutes before injection by the administration of the serotonin uptake blocker fluoxetine. The opiate antagonist does not modify the increase in blood level of prolactin induced by (?) ?$\text{m}$-chlorohenylpiperazine. Naloxone itself does not reduce the increase in plasma level of corticosterone induced by 5-hydroxytryptophan, 5-hydroxytryptophan +fluoxetine or (?)?$\text{m}$-chlorophenylpiperazine.The results suggest that endogenous opioids may be involved in the increase in serum level of prolactin induced by 5-hydroxytryptophan and also indicate the existence of different serotonergic neurotransmitter circuits capable of modulating the release of prolactin and corticosterone. A mutual interplay between serotonergic and opiate neurons may be involved in controlling the release of prolactin, but such an interplay does not seem to occur in the secretion of corticotrophin-releasing hormone.     

d-Amphetamine raises serum prolactin in man: evaluations after chronic placebo, lithium and pimozide treatment.

One of the major biochemical effects of d-amphetamine is the release and uptake inhibition of dopamine (DA). We measured the effect of d-amphetamine upon prolactin release which is inhibited by DA and stimulated by serotonin. d-Amphetamine (20 mg i.v.) significantly raised the serum prolactin levels of drug-free schizophrenic patients over preinfusion levels and levels following a paired placebo lactose infusion. Amphetamine infusions were repeated after both chronic DA blockade with pimozide and after chronic lithium treatment that has been reported to attenuate amphetamine effects. These chronic pretreatments did not prevent significant increases in prolactin following d-amphetamine infusions. Pimozide raised preinfusion prolactin levels but lithium had no effect. Further studies are needed to clarify the d-amphetamine-induced rise in prolactin.     

Clozapine increases rat serum prolactin levels.

Clozapine differs from other anti-psychotic drugs in that is produces little or no extrapyramidal side effects. The effects of clozapine on rat brain dopamine differ markedly from those of the neuroleptic drugs. The neuroleptics increase rat serum prolactin levels which has been attributed to their dopamine receptor blocking properties. We found that clozapine markedly increased serum prolactin levels in male rats when injected intraperitoneally in doses of 5, 10, 50 and 100 mg/kg. Serum prolactin levels after 5 mg/kg clozapine were significantly less than in rats given 10, 50 and 100 mg/kg which did not significantly differ from each other. Serum prolactin after 10 mg/kg clozapine was significantly greater than after chlorpromazine, 5 mg/kg and haloperidol, 0.5 mg/kg. The increases in serum prolactin are attributed to clozapine's ability to produce dopamine blockade or to inhibit nerve impulse-dopamine release, or both. The capacity of clozapine to affect brain serotonin and norepinephrine metabolism and its strong anti-cholinergic properties are probably not involved in its ability to increase serum prolactin.     

The influence of estrogen on plasma prolactin levels induced by thyrotrophin releasing hormone (IRH), clonidine and serotonin in ovariectomized rats.

Prolactin levels were determined in the plasma of ovariectomized and ovariectomized estrogen treated rats by RIA following intraarterial injection of TRH, (1 and 10 μg/rat), clonidine (5 mg/kg) and serotonin (10 mg/kg). In ovariectomized rats, TRH had no effect on plasma prolactin whereas serotonin and clonidine induced slight and moderate increases respectively. In contrast, TRH induced a significant increase in plasma prolactin in estrogen-treated rats while the effects of the other two agents were enhanced only slightly (clonidine) or very markedly (serotonin). These results indicate that the prolactin-releasing activity of TRH is dependent on estrogen and that estrogen differentially affects noradrenergic and serotonergic components of the neuroendocrine mechanism that controls prolactin. It is also suggested that clonidine and serotonin probably do not increase plasma prolactin by releasing endogenous TRH.     

Evidence that serotonin neurons stimulate secretion of prolaction releasing factor.

The purpose of the present study was to determine if serotonin was stimulatory to prolactin release by inhibition of the dopaminergic system or by stimulating release of a prolactin releasing factor (PRF). We measured the amount of prolactin secreted after administration of 30 mg/kg of 5-hydroxytryptophan (5-HTP) to male rats pretreated with fluoxetine (10 mg/kg) and compared it with the amount of prolactin released in male rats treated with αmethyl-p-tyrosine methyl ester (αMT) or various dopamine receptor blocking agents. In every experiment the serotonergic stimulus provided by 5-HTP in fluoxetine-pretreated rats released considerably more prolactin than did treatment with αMT or dopaminergic blockers. We conclude that serotonin releases prolactin not by inhibiting dopaminergic neurons but rather by stimulating the release of PRF.     

Potential role of prolactin in antipsychotic-mediated association of schizophrenia and type 2 diabetes

It remains unclear why atypical antipsychotics confer a risk for hyperglycemia compared to typical antipsychotics. Atypical antipsychotics antagonize dopamine receptors-2 (D(2)) and serotonin (5-HT) receptors-2, while typical antipsychotics antagonize only D(2) receptors. We aimed at elucidating the mechanistic differences between the role of typical and atypical antipsychotics on prolactin levels and glucose regulation. A Medline search was conducted during 2010 using the search terms type 2 diabetes (T2D), typical/atypical antipsychotics, schizophrenia, prolactin, and serotonin. We discuss the effect of typical and atypical antipsychotics on prolactin levels and glucose regulation. Given that prolactin is under negative control by dopamine and positive control by serotonin, typical antipsychotics induce elevations in prolactin, while atypical antipsychotics do not. Research studies show protective effects of prolactin on T2D. We hypothesize that the difference in induction of T2D between typical and atypical antipsychotics is due to the antipsychotic receptor binding mediated effect in changes in prolactin levels.     

Effects of tranylcypromine treatment on neuroendocrine, behavioral, and autonomic responses to tryptophan in depressed patients

Effects of intravenous administration of the serotonin precursor tryptophan (TRP) on serum prolactin, neuromotor function, subjective mood, and blood pressure and pulse were determined in nine depressed patients before and during placebo-controlled treatment with the monoamine oxidase inhibitor (MAOI) tranylcypromine. Tranylcypromine significantly increased the prolactin response to TRP. Four patients developed a distinctive neuromotor syndrome following TRP during tranylcypromine, but not placebo, treatment. Symptoms included hyperreflexia, ankle clonus, nystagmus, incoordination, tremor, myoclonic jerks, and nausea. There were no differences in peak prolactin, mood, or autonomic responses between patients with and without the syndrome, but those with the syndrome had received active tranylcypromine for a significantly shorter duration. Tranylcypromine had little effect on TRP-induced changes in mood or autonomic function, except for a modest enhancement of the TRP-induced rise in diastolic blood pressure. These results suggest that tranylcypromine treatment may enhance serotonin function in depression.     

The neuropharmacology of prolactin secretion elicited by 3,4-methylenedioxymethamphetamine ("ecstasy"): a concurrent microdialysis and plasma analysis study

3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug "ecstasy". Racemic MDMA (S,R(+/-)-MDMA) and its stereoisomers elicit complex spectrums of psychobiological, neurochemical, and hormonal effects. In this regard, recent findings demonstrated that S,R(+/-)-MDMA and its stereoisomer R(-)-MDMA elicit increases in striatal extracellular serotonin levels and plasma levels of the hormone prolactin in rhesus monkeys. In the present mechanistic study, we evaluated the role of the serotonin transporter and the 5-HT(2A) receptor in S,R(+/-)-MDMA- and R(-)-MDMA-elicited prolactin secretion in rhesus monkeys through concurrent microdialysis and plasma analysis determinations and drug interaction experiments. Concurrent neurochemical and hormone determinations showed a strong positive temporal correlation between serotonin release and prolactin secretion. Consistent with their distinct mechanisms of action and previous studies showing that the serotonin transporter inhibitor fluoxetine attenuates the behavioral and neurochemical effects of S,R(+/-)-MDMA, pretreatment with fluoxetine attenuated serotonin release elicited by either S,R(+/-)-MDMA or R(-)-MDMA. As hypothesized, at a dose that had no significant effects on circulating prolactin levels when administered alone, fluoxetine also attenuated prolactin secretion elicited by S,R(+/-)-MDMA. In contrast, combined pretreatment with both fluoxetine and the selective 5-HT(2A) receptor antagonist M100907 was required to attenuate prolactin secretion elicited by R(-)-MDMA, suggesting that this stereoisomer of S,R(+/-)-MDMA elicits prolactin secretion through both serotonin release and direct agonism of 5-HT(2A) receptors. Accordingly, these findings inform our understanding of the neuropharmacology of both S,R(+/-)-MDMA and R(-)-MDMA and the regulation of prolactin secretion.     

Injections of alpha-melanocyte stimulating hormone affect pineal serotonin, melatonin and N-acetyltransferase activity

To determine if exogenously administered alpha-melanocyte stimulating hormone (alpha-MSH) affects nighttime pineal N-acetyltransferase activity, pineal levels of 5-hydroxytryptophan, serotonin and melatonin, and plasma prolactin levels, adult male hamsters were injected at 1900 hr (lights out 2000-0600 hr) with two doses of the peptide and killed at 0300 hr. The low dose of alpha-MSH (200 ng) produced a significant fall in pineal serotonin, pineal NAT activity and plasma prolactin values. The high dose of the peptide (20 micrograms) increased circulating prolactin titers and pineal serotonin levels and caused a concomitant decrease in pineal melatonin levels.     

Changes in serum titres of prolactin, somatotropin and thyrotropin induced by fenfluramine in humans

An increase of serum titres of prolactin was observed upon acute and chronic administration of fenfluramine. In acute treatment also STH levels were enhanced. No changes were observed in TSH titres. The authors relate the endocrine effect to serotonin turnover stimulation in central nervous system.     

Serotoninergic drugs affect prolactin and growth hormone secretion in the domestic fowl

Adult fowl of both sexes injected with the monoamine oxidase inhibitor pargyline showed elevated circulating prolactin concentrations and reduced growth hormone concentrations. Young cockerels injected with the serotonin agonist quipazine and the antagonist methysergide showed responses consistent with a serotoninergic stimulatory control of prolactin. Injection of the serotonin precursor tryptophan and the serotonin re-uptake blocker imipramine resulted in elevated prolactin and reduced growth hormone levels. The similarities and differences in the control of prolactin and growth hormone in birds and mammals were discussed.     

Effect of an anti-substance P serum on prolactin and gonadotropins in hyperprolactinemic rats

The effects of the acute injection of a rabbit anti-substance P serum (ASPS) were studied in normal rats and rats with hyperprolactinemia induced by 5-hydroxytryptophan and estradiol given as a short or chronic treatment. The anti-substance P serum decreased the release of prolactin induced by 5-hydroxytryptophan when this serotonin precursor was injected 24 h, but not 1 h, after the administration of the antiserum. ASPS reduced the hyperprolactinemia induced by short and chronic treatment with estradiol in castrated rats. This effect was observed 24 h after the injection of the antiserum. On the other hand, the injection of ASPS induced a significant decrease in LH levels in serum of intact male rats injected with 5-hydroxytryptophan 24 h after ASPS, and in castrated rats treated with short-term and chronic administration of estradiol, 24 h after the injection of the antiserum. These results suggest that substance P may have a role in the control of prolactin secretion and could play a part in the hyperprolactinemic effects of estradiol. On the other hand, substance P, under certain circumstances, may stimulate LH release.