Chlorpromazine, haloperidol, metoclopramide and domperidone release prolactin through dopamine antagonism at low concentrations but paradoxically inhibit prolactin release at high concentrations

1. The effects of chlorpromazine, haloperidol, metoclopramide and domperidone on the release of prolactin from perfused columns of dispersed rat anterior pituitary cells were studied. 2. Chlorpromazine, haloperidol, metoclopramide and domperidone antagonized the dopamine-mediated inhibition of prolactin release at low concentrations. 3. Each dopamine antagonist displaced the dose-response curve for dopamine-induced suppression of prolactin release to the right in a parallel manner. 4. At higher concentrations, the four drugs became less effective as dopamine antagonists. 5. At high concentrations in the absence of dopamine, chlorpromazine, haloperidol, metoclopramide and domperidone paradoxically suppressed prolactin secretion by an unknown mechanism.     

Nafazatrom, an arachidonate metabolism inhibitor, decreases prolactin and GH release

Nafazatrom, an inhibitor of arachidonate metabolism by the lipoxygenase enzymes, decreases basal prolactin and growth hormone release in a concentration-dependent manner without significantly affecting the synthesis of either hormone. It is required that nafazatrom be incubated with pituitary cells for approximately 2 h for this effect to become evident; the blockade increases in magnitude for up to 4 h. Nafazatrom blocks the increase in prolactin release caused by the releasing factors TRH and angiotensin II and the increase in prolactin and growth hormone release due to the calcium channel activator maitotoxin. These data suggest that the lipoxygenase products of arachidonate metabolism may be important mediators in basal and secretagogue-induced release of prolactin and growth hormone.     

Antipsychotic drugs stimulate prolactin release

Antipsychotic drugs have been found to markedly stimulate prolactin secretion in male and female rats. The amount of prolactin released was greater in females than in males. Most non-antipsychotic phenothiazines failed to alter prolactin. These results imply that the dopamine receptor that inhibits prolactin release may be similar to the dopamine receptor involved in the action of antipsychotic drugs.     

Naltrexone blocks nicotine-induced prolactin release

Two receptor populations involved in the release of prolactin were examined in conscious, freely moving, male rats bearing indwelling jugular cannulae. The intravenous administration of either nicotine or morphine increased plasma prolactin levels. Pretreatment with the nicotinic antagonist mecamylamine blocked the prolactin response to nicotine only. In contrast, the opiate antagonist naltrexone blocked the prolactin response to both nicotine and morphine. These findings indicate that the nicotine stimulated release of prolactin is dependent not only on functional nicotinic cholinergic receptors but on opiate receptors as well. This suggests that nicotine and morphine release prolactin via a common pathway containing nicotinic cholinergic and opiate synapses in series.     

Effect of chronic lead treatment on brain dopamine synthesis and serum prolactin release in the rat

The effect of chronic dietary lead exposure on brain striata dopaminergic transmission was studied in rats by measuring dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Serum prolactin (PRL) concentration was also measured. The results show a decreased striatal dopamine synthesis and increased serum PRL concentrations.     

Lithium increases 5-HT-mediated prolactin release

The effects of short-term (3–4 days) lithium treatment on the prolactin responses to intravenous clomipramine (0.1 mg/kg), metoclopramide (5 g/kg) and haloperidol (2.5–5 g/kg) were assessed in male volunteers. Prolactin responses to clomipramine were significantly enhanced by lithium while those following administration of haloperidol and metoclopramide were not significantly altered. Lithium did not change the cortisol response to clomipramine. The results suggest that lithium may selectively enhance 5-HT mediated prolactin release. These data are consistent with the hypothesis that synergistic effects of lithium and clomipramine on brain 5-HT function may be involved in their therapeutic effect in resistant depression.     

Reserpine and sleep

Recent studies of the effects of reserpine on human sleep have reported increased rapid eye movement (REM) sleep, and decreased slow-wave (SW) sleep. These results are relevant to theories linking serotonin and the catecholamines to the control of different stages of sleep. However, since reserpine causes release and subsequent depletion of both monoamines, it is difficult to relate changes in sleep profiles to specific alterations in one or the other amine system. The results to be reported here, when compared to those obtained with other treatments which affect the biogenic amines, encourage the view that level and turnover of serotonin are the primary mediators for reserpine-induced modifications of sleep. In two separate experiments, EEG sleep patterns from 20 male Ss were examined following single and repeated oral doses (1 mg) of reserpine. In the single-dose study, reserpine caused increased REM, and decreased SW sleep, effects which became statistically significant on the post-medication (P-M) recovery session. These changes were accompanied by reduced frequency per minute of sigma spindles (stage 2) decreased eye-movement density (stage REM) and a tendency toward increased brief arousals, especially during stage REM. Examination of parameters of the REM cycle revealed that the potentiation of REM sleep was due to its reduced latency of onset, and more frequent cyclic occurrence, not to increased duration of REM episodes. The results of the repeated-dose study replicated and amplified those of the first experiment, showing that medication caused a progressive increase in the amount of stage REM, accompanied by a simultaneous loss of SW sleep. The increase in REM was again due to acceleration of its cycle rather than lengthening of its episodes. During medication, epochs of stage REM were increasingly interrupted by brief arousals, with a simulteneous decline in the density of rapid eye movements. Most of these reserpine effects persisted into the P-M recovery session.The acceleration of the REM cycle, loss of SW sleep, decrease in sigma spindles and increase in brief arousals indicate that the acute effects of reserpine on human sleep are in the direction of activation, and the persistence of most of these alterations into the P-M session implies that they are due to depletion of one or both monoamines. However, comparison of reserpine effects on sleep with those induced by precursors and blockers of serotonin, and by monoamine oxidase inhibitors suggests that the loss of SW sleep may have resulted from depletion of serotonin, whereas acceleration of the REM cycle may have been caused by a compensatory increase in its rate of synthesis.This study was supported in part by USPHS grant No. MH 10844-05 of the National Institute of Mental Health.We thank Orvis H. Rundell, William J. Griffiths and Lawrence C. Cowden for their technical assistance and management of subjects, and Rosa Coulter for her contributions to analysis of data.     

Baclofen, a GABA derivative, inhibits stress-induced prolactin release in the rat

The effect of baclofen, beta-(4-chlorophenyl)GABA, on prolactin secretion was investigated in rats under several experimental conditions. In adult male rats subjected either to immuobilization, ether, swimming or cold stress there was a rapid increase of serum prolactin levels; acute pretreatment with baclofen, 10 mg/kg i.p. inhibited the hormone response to all these stresses. The same blocking effect of the drug was observed in prepubertal male and female rats and in adult gonadectomized animals. In basal conditions, i.e. in undisturbed male rats, baclofen did not change the hormone titers significantly. Taken together our results indicate that baclofen blocks prolactin release when release of the hormone is dynamically stimulated by stress and this effect is relatively independent of the endocrine status of the rat.     

ECT-induced prolactin release: Effect of sex,electrode placement and serotonin uptake inhibition

We and others have previously reported that the non-specific serotonin receptor antagonist methysergide inhibits the PRL response to ECT wheras the 5HT-2 antagonists ketanserin and ritanserin have no effect. In the present study the effect of serotonin uptake inhibition on this neuroendocrine response was examined in two separate placebo-controlled experiments. According to our results neither clomipramine (25 mg orally) nor fluoxetine (20 mg orally) affected the PRL response to ECT. An analysis of the placebo day data from 32 subjects indicates that a high PRL response to ECT is associated with female sex and bilateral electrode placement.     

Reserpine,hydrochlorothiazide and pituitary-gonadal hormones in hypertensive patients

Summary Sex histories and serum samples were obtained from 27 hypertensive men before and after 3 months of therapy with either 100 mg of hydrochlorothiazide or 0.25 mg of reserpine daily. Sera were analyzed for testosterone, dihydrotestosterone, estradiol, luteinizing hormone and prolactin. Both drugs effectively lowered blood pressure. The incidence of impaired sexual performance was low and insignificantly different in the two treatment groups. There were no significant changes in serum hormone concentrations as a result of drug therapy.     

Casticin, a flavonoid isolated from Vitex rotundifolia, inhibits prolactin release in vivo and in vitro

Aim:

To investigate the anti-hyperprolactinemia activity of casticin, a flavonoid isolated from Vitex rotundifolia, and elucidate its molecular mechanism.

Methods:

Hyperprolactinemia (MIHP) was induced by administration of metoclopramide dihydrochloride (50 mg/kg, tid, ip, for 10 d) in SD rats and the primary pituitary cells were prepared from the pituitary glands of the SD rats. Prolactin concentrations were measured using a radioimmunoassay. Cell viability was measured using an MTT assay. The mRNA expression of estrogen receptor alpha and beta in rat pituitary cells was measured using semi-quantitative RT-PCR analysis.

Results:

The level of serum prolactin in the MIHP model group was 2.1 fold higher than that in the untreated control group (P<0.01). Casticin (10, 20, and 40 mg/kg, ip, for 7 d) reduced serum prolactin levels by 33.9%, 54.3%, and 64.7%, respectively (P<0.01). The positive control drug bromocriptine 1 mg/kg decreased the serum prolactin concentration in MIHP rats by 44.9%. 17β-Estradiol (E2) significantly increased the proliferation of pituitary cells and casticin (1 and 10 μmol/L) markedly inhibited E2-induced pituitary cell proliferation by 27.7% and 42.1%, respectively. Stimulation of pituitary cells with E2 increased prolactin secretion into the cell culture supernatants, and casticin (0.1, 1, and 10 μmol/L) significantly inhibited the prolactin release stimulated by E2 in a concentration-dependent manner. Casticin (1 and 10 μmol/L) significantly inhibited ERα mRNA expression in pituitary cells stimulated with E2 (P<0.01) but increased ERβ mRNA expression at a concentration of 10 μmol/L (P<0.01). However, casticin had no effects on proliferation and prolectin release of the unstimulated primary pituitary cells in vitro.

Conclusion:

Casticin inhibited the release of prolactin from pituitary cells of SD rats stimulated with E2 in vivo and in vitro. These effects might be related with inhibiting the ERα mRNA expression and increasing the ERβ mRNA expression.     

Ritanserin,a 5-HT2 receptor antagonist,does not modify ECT-induced prolactin release

The effect of pretreatment with ritanserin, a potent and selective serotonin-S₂ (5-HT₂) receptor antagonist, on the prolactin (PRL) response to electroconvulsive therapy (ECT) was studied in seven female patients suffering from major depressive disorder. They were given either ECT alone, or ECT after 10 or 20 mg ritanserin PO, and PRL was estimated in blood samples taken at times –5, 0, +5, +15, +30 and +60 min. The PRL responses after drug administration were not different from the responses after ECT alone. We conclude that, if serotonergic mechanisms are involved in the ECT-induced PRL increase, this neuroendocrine response seems to be rather a 5-HT₁ than 5-HT₂ receptor mediated event.     

Metergoline and cyproheptadine suppress prolactin release by a non-5-hydroxytryptaminergic, non-dopaminergic mechanism.

Isolated atria of guinea-pigs were treated with veratrine until the initial signs of toxicity were seen. Ouabain was then added cumulatively, starting with a threshold inotropic concentration, 50 nM, until the tissue became dysrhythmic. It was found that a concentration of ouabain which by itself gave a positive inotropic effect of only 3%, significantly enhanced the toxicity of veratrine. Veratrine had no effect on the (Na+ + K+)-adenosine triphosphatase ((Na+ + K+)-ATPase) enzyme isolated from guinea-pig ventricle. The conclusion drawn is that at threshold inotropic concentrations of ouabain it is likely that the (Na+ + K+)-ATPase is inhibited rather than stimulated.     

Modulating role of lithium on dopamine turnover,prolactin release,and behavioral supresensitivity following haloperidol and reserpine

The effects of haloperidol, reserpine, and concomitant lithium were evaluated in biochemical, endocrine, and behavioral studies in the rat. Concomitant administration of a chronic regimen of haloperidol and lithium did not prevent the development of tolerance as noted by dopamine metabolites in the striatum or olfactory tuberculum. Nor did chronic lithium alter behavioral response in rats treated with reserpine and challenged with the dopamine agonist apomorphine. Additionally, prolactin release was increased by haloperidol, but was not altered by acute or chronic lithium treatment. These findings are discussed in the light of present knowledge of pre- and postsynaptic receptor changes and the effects of lithium.     

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Reserpine rigidity and adrenergic neurones

The possible mechanism of reserpine-induced rigidity in the rat has been studied. Tetrabenazine which produces a loss of brain amines like reserpine also produced rigidity. Reserpine-induced rigidity was abolished most effectively by monoamine oxidase inhibitors particularly tranylcypromine. Alpha-methyl-dopa and α-methyl-m-tyrosine pretreatment reduced rigidity but it was unaffected by DOPA and 5-HTP. The pharmacology of reserpine rigidity resembled that of an isolated adrenergic synapse, the guinea pig hypogastric nerve vas deferons preparation. It is concluded that reserpine rigidity might be due to a loss of brain dopamine or to an increase in deaminated metabolites, or both.