Phospholipid liposomes and prolactin secretion: Effects on spontaneous and drug-induced hyperprolactinaemia

Bovine brain phospholipid liposomes (BC-PL) reduce plasma prolactin (PRL) levels in humans after acute administration and counteract the metoclopramide- and sulpiride-induced hyperprolactinaemia. However, BC-PL, like nomifensine, a dopaminergic compound, does not influence TRH-induced hyperprolactinaemia. Moreover BC-PL and nomifensine reduce plasma PRL levels in hyperprolactinaemic PCO syndromes but not in PRL secreting pituitary adenomas. The results obtained indicate that BC-PL antagonizes the DA blockade-induced hyperprolactinaemia and that the main site of action of BC-PL seems to be at the hypothalamic level; however a concomitant pituitary effect cannot be ruled out.     

Disturbed prolactin responses to dopamine-related substances in patients with acromegaly and hyperprolactinemia

We undertook this study, because conflicting data were reported about the dopaminergic regulation of prolactin (PRL) secretion in patients with acromegaly and hyperprolactinemia. In order to clarify the dopaminergic regulation of PRL secretion in patients with acromegaly and hyperprolactinemia, the effects of nomifensine, a central dopamine agonist, FK 33-824, a centrally antidopaminergically acting agent, and domperidone, a peripheral dopamine antagonist, on plasma PRL in these patients were studied. The results were compared with those observed in normal subjects and hyperprolactinemic patients, with or without a pituitary tumor. Nomifensine did not lower the PRL levels and FK 33-824 did not raise the PRL levels in acromegalic patients. In hyperprolactinemic patients, nomifensine did not lower the PRL levels and FK 33-824 failed to raise the PRL levels. Domperidone did not increase PRL in about a third of acromegalic patients, while TRH increased PRL in the all normoprolactinemic acromegalic patients. These results suggest that in acromegalic patients there may be a disturbance in dopamine related neurotransmission and that such disorders also seem to be present in patients with hyperprolactinemia, with or without a pituitary tumor.     

Effect of pretreatment with metoclopramide on plasma prolactin response to methergoline

The Authors examined 20 voluntary women without endocrine diseases. The women took 4 mg of metergoline orally and 30-60-90-120-180-240 minutes after the medicament was given the serum prolactin levels were tested. After 3 weeks, 14 among 20 subjects repeated the test assuming during the 3 days before 50 mg of metoclopramide orally once a day. The Authors found a remarkable decline of prolactin serum levels after metergoline administration in all subjects. After metoclopramide administration prolactin serum levels increased meaningly. Metergoline administration gave again considerable fall of prolactin serum levels in the 14 subjects. From the data the Authors affirm that metergoline inhibits prolactin secretion with an antiserotonine action     

The effect of dexamethasone on TSH and prolactin secretion after TRH stimulation

Serum thyrotropin (TSH) and prolactin levels were measured after intravenous administration of 400 μg of synthetic thyrotropin-releasing hormone (TRH) in 13 normal subjects and six hypothyroid patients before and after three days of administration of dexamethasone 2 mg per day. In the normal subjects dexamethasone suppressed baseline serum levels and secretion of TSH after TRH stimulation. On the other hand, it had no effect on the hypothyroid patients. In the control group dexamethasone also suppressed baseline serum levels but not secretion of prolactin after TRH stimulation. Dexamethasone had no effect on prolactin levels in the hypothyroid group. It is concluded that in normal patients short-term administration of dexamethasone has an inhibitory effect on TSH secretion at the pituitary level. As for prolactin, our results could indicate that TRH is a more potent stimulator of prolactin secretion than of TSH secretion, or that TSH and prolactin pituitary thresholds for TRH are different.     

Characterization and Pharmacological Responsiveness of Dopamine Release Recorded by Microdialysis in the Substantia Nigra of Conscious Rats

The extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid in the substantia nigra (SN) and striatum was estimated by microdialysis. The dialysate content of DA from the SN was recorded during infusion of a DA uptake blocker (nomifensine; 5 mumol/L) dissolved in the perfusion fluid. Perfusion of tetrodotoxin (1 mumol/L) produced a virtually complete disappearance of nigral and striatal DA release. Dendritic as well as terminal release of DA was inhibited for several hours when the nerve impulse flow in dopaminergic neurons was blocked by systemic administration of gamma-butyrolactone (750 mg/kg, i.p.). The systemic administration (0.3 mg/kg, i.p.) as well as infusion (1 mumol/L) of the D2 agonist (-)-N-0437 [2-(n-propyl-N-2-thienylethylamino)-5-hydroxytetralin] produced a significant decrease in the release of DA in both the striatum and the SN. DA levels were recorded in the striatum both with and without addition of nomifensine to the perfusion fluid. The decrease in the striatum after (-)-N-0437 was suppressed in the presence of nomifensine. Infusion (1 mumol/L) as well as systemic administration (40 mg/kg) of sulpiride caused a similar increase in the release of striatal DA; this increase was, in both experiments, potentiated by nomifensine coinfusion. Sulpiride administration induced a small increase in the release of nigral DA. Infusion of (-)-N-0437 or (-)-sulpiride into the nigra caused a moderate decrease and increase, respectively, of striatal DA level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Time course of the insensitivity of prolactin release to morphine administration in the lactating female rat

The effect of morphine on circulating levels of prolactin and growth hormone (GH) in the lactating female model was determined at various time intervals following the termination of suckling. Morphine administration did not produce an increase in prolactin levels when dams remained suckling. Four days after suckling was terminated, 50% of the dams tested showed a morphine induced prolactin increase. The prolactin secretory response to morphine gradually returned in dams, so that after 8 days of non-suckling, all animals tested showed a morphine induced prolactin increase. Consistent with the lack of prolactin stimulation, the tuberoinfundibular dopaminergic (TIDA) neurons, were insensitive to the morphine induced inhibition of activity during lactation. In contrast, circulating levels of GH were increased in these dams following morphine administration. These results suggest that the lactating female rat is insensitive to the mu mediated stimulation of prolactin release while suckling. However, sensitivity begins to return following at least 4 days of non-suckling.     

Involvement of Opioid Receptor Subtypes in Both Stimulatory and Inhibitory Effects of the Opioid Peptides on Prolactin Secretion During Pregnancy

1. We have previously demonstrated the existence of a dual neuromodulatory regulation of prolactin secretion by the opioid system. In the present work, we evaluated the opioid receptor subtypes involved in both the stimulatory and the inhibitory regulation of prolactin secretion in pregnant rats. 2. Specific opioid agonists and antagonists were administered intracerebro ventricular (i.c.v.) to rats on day 3 and on day 19 pregnancy in rats of pretreated with mifepristone. Blood samples were obtained after decapitation at 12.00 and 18.00 h. Serum prolactin levels were measured by RIA. 3. The mu-selective agonist DAMGO and beta-endorphin caused a significant increase in serum prolactin secretion on day 3 of pregnancy, during the diurnal surge and intersurge period. Pretreatment with naloxone prevented the increase on prolactin levels induced by DAMGO. The administration of U-50,488, a kappa-selective agonist or DPDPE, a delta-selective agonist, did not modify serum prolactin concentration while the mu1-antagonist naloxonazine reduced significantly serum prolactin levels. On day 19 of pregnancy, the release of prolactin induced by mifepristone was significantly increase by naloxonazine, while the kappa-antagonist nor-binaltorfimine induced only a small but significant increase. No effect was observed after administration of the delta-antagonist naltrindole. 4. We conclude that the mu-opioid receptor seems to be more specifically involved in both the stimulatory and inhibitory regulation by the opioid system on prolactin secretion during pregnancy. The increase on serum prolactin levels on day 3 after administration of DAMGO and beta-endorphin may suggest the participation of other regulatory mechanisms as the dopaminergic and serotoninergic systems. On day 19, only the endogenous ligands delta did not participate in the regulation of prolactin secretion, while the participation of the kappa-opioid receptor was significantly less effective than the endogenous ligand mu. Our results provide evidences of an important role of the opioid system through specific receptors on the regulation of prolactin secretion during early and late pregnancy.     

Plasma gonadotropin,prolactin levels and hypothalamic tyrosine hydroxylase activity in rats during estrous cycle,after overiectomy and after blockade of catecholamine biosynthesis

Plasma gonadotropin, prolactin levels and hypothalamic tyrosine hydroxylase activity were evaluated at 0900, 1200 and 1700 h during diestrus, proestrus and estrus, ovariectomized and after systemic administration of reserpine or α-methyl p-tyrosine, which interfere with catecholamine biosynthesis, in rats. Gonadotropin and prolactin levels showed peak values during the afternoon of proestrus, while hypothalamic tyrosine hydroxylase activity was markedly lowered at 1200 on proestrus. Gonadotropin levels were slightly lowered whereas prolactin concentrations and hypothalamic tyrosine hydroxylase activity were significantly increased by reserpine. Depletion of hypothalamic dopamine by reserpine apparently resulted in significant elevation of prolactin levels which inturn induce tyrosine hydroxylase. Gonadotropin levels and hypothalamic tyrosine hydroxylase activity were significantly suppressed after the administration of α-methyl p-tyrosine. Prolactin levels, however, were elevated significantly. These results indicate that catecholamines are involved in the control of gonadotropin and prolactin release during estrous cycle and inhibition of catecholamines biosynthesis by α-methyl p-tyrosine could result in suppression of gonadotropin levels, whereas removal of tonic inhibition of hypothalamic dopamine by α-methyl-p-tyrosine elevate prolactin levels.     

Cadmium does not inhibit pulsatile prolactin secretion through TRH

This work was undertaken to analyse the effects of acutecadmium administration on the pulsatile patternof prolactin release, in adult male rats.For this purpose, animals were cannulated 40 h before the experi-mentto allow a continuousblood withdrawal. Two hours after the administration of one dose of cadmiumchloride (4.5 mg kg1 ), the pulsatile pattern of prolactin, during three hours, was studied. The effects oftwopulses of thyrotropin-releasing hormone (TRH) (1 mg per rat), given 60 and 120 min afterstarting the periodof blood sampling, were studied. The mean values of prolactin during thebleeding period and the absolutepulse amplitude were decreased by acute cadmium chlorideadministration. However, no changes in anyother parameters of prolactin pulsatility were observed.TRH administration to control rats increased meanprolactin levels, and absolute andrelative pulse amplitudes, but decreased the mean half-life of the hormone.In animals pretreated withcadmium, TRH increased the mean levels of prolatin, and absolute and relativeamplitudes ofthe hormone pulses. No other parameter studied was changed by TRH in cadmiumpretreatedrats. These data suggest that acute administration of cadmium did not inhibit thepulsatile prolactin releasethrough TRH.     

Lack of involvement of dopamine and serotonin during the orphanin FQ/Nociceptin (OFQ/N)-induced prolactin secretory response

The purpose of these studies was to examine possible mechanisms of Orphanin FQ/Nociceptin (OFQ/N)-induced prolactin release. We investigated the involvement of the dopaminergic neurons by quantifying DOPAC:DA levels in the median eminence and neurointermediate lobe following central administration of OFQ/N to female Sprague-Dawley rats. To specifically determine the involvement of the tuberoinfundibular dopaminergic neurons, immunocytochemical studies were conducted to visualize c-fos protein expression in the arcuate nucleus following central administration of OFQ/N. In addition, the role of serotonergic activation was examined in dose response studies using the selective serotonin antagonist ritansarin and the nonselective antagonist metergoline. Finally, the pharmacological specificity of the prolactin response was examined by pretreating animals with [Nphe1] NC (1-13)NH2, a drug reported to antagonize OFQ/N effects. The results of these studies indicate that the increase in prolactin release following central administration of OFQ/N does not inhibit tuberoinfundibular, tuberohypophyseal or periventricular hypophysial dopaminergic neuronal activity at 10 min after drug administration, a time when prolactin levels were significantly elevated. Furthermore, serotonergic activation is not involved since pharmacological blockade of serotonergic receptors did not alter the prolactin secretory response to OFQ/N. NC (1-13)NH2 did not antagonize the stimulatory effects of OFQ/N on prolactin secretion. The neural effects of OFQ/N on dopaminergic neuronal activity may occur following a different time course than that of the prolactin increase.     

Metachlopromide-induced hyperprolactinemia fails to affect ovarian cyclicity in the common marmosets (Callithrix jacchus)

Intramuscular administration of metachlopromide (2.5, 5, and 10 mg) induced a dose-dependent increase in plasma prolactin levels. The magnitude and duration of metachlopromide-induced hyperprolactinemia were also dose related. However, metachlopromide treatment (5 mg/day) for 60 days failed to affect ovarian function in the common marmoset as evidenced by ovulatory plasma estradiol and progesterone profiles. During the pretreatment cycle, there was no consistent pattern in plasma prolactin levels depending on the stage of cycle. During lactation, higher levels of plasma prolactin were observed.     

Effects of metachlopromide-induced hyperprolactinemia on serum testosterone and its response to hCG in adult male common marmosets (Callithrix jacchus)

Intramuscular administration of metachlopromide (2.5, 10, and 25 mg) induced increase in serum prolactin levels. Following 10 and 25 mg dose levels, prolactin levels were elevated at least for 8 hr. Single administration of metachlopromide failed to affect the nocturnal rise in circulating levels of testosterone. Daily treatment of metachlopromide (10 mg) for 30 days suppressed the nocturnal elevation of testosterone on day 28 of treatment. However, the hCG-stimulated testosterone production on day 30 was unaffected. The results of the present study demonstrate that metachlopromide-induced hyperprolactinemia in adult male common marmosets affects the hypothalamo-pituitary axis without any effect on testicular response to hCG.     

Effect of diclofenac on plasma levels of immunoreactive prolactin, follicle stimulating hormone, luteinizing hormone, thyrotropin, and beta-endorphin in humans

Prostaglandins have been shown to modulate the secretion of several pituitary hormones, suggesting that therapeutic doses of nonsteroidal anti-inflammatory drugs may change basal hormone levels. In this study, plasma levels of prolactin, follicle stimulating hormone, luteinizing hormone, thyrotropin and beta-endorphin were determined in 6 healthy men after administration of diclofenac, a prostaglandin synthesis inhibitor. The subjects were given 75 mg intramuscularly and 50 mg orally at 08.00 h the first day, 50 mg orally at 08.00, 12.00 and 20.00 h the second day and an additional 50 mg orally at 08.00 h the third day. Blood samples were collected throughout these 3 days. Diclofenac resulted in a significant and sustained decrease in plasma level of prolactin (p less than 0.005). The other hormones did not demonstrate significant change following diclofenac administration. These data suggest that administration of a prostaglandin synthesis inhibitor, such as diclofenac, selectively alters basal pituitary secretion of prolactin in humans without a detectable effect on plasma levels of other pituitary hormones. This study supports the hypothesis that prostaglandins are necessary for maintaining basal level of prolactin secretion in man.     

Effect of ACTH and glucocorticoids on plasma prolactin levels in the male rat

Relationships between prolactin and adrenal secretion were studied in the adult male rat by different experimental approaches. Administration of a long acting 1-24 ACTH preparation during 11 days induced a significant decrease in plasma prolactin levels. Adrenalectomy on the contrary resulted in an increase of prolactin levels that were not affected by ACTH treatment. Dexamethasone administration to intact or adrenalectomized animals resulted in a significant reduction of plasma prolactin in both cases. In order to elucidate if the inhibitory effect of the adrenal stimulation on prolactin was mediated through the blockade of endogenous ACTH, stimulation of hypothalamic-pituitary-adrenal axis with chronic intermittent immobilization stress was performed. Stress induced a significant elevation in plasma corticosterone levels, together with a decrease in prolactin values. These data indicated that the inhibitory role of ACTH and stress on prolactin secretion was mediated through the adrenal glucocorticoid stimulation.     

Inhibition of food intake in the rat

The effects of single oral administrations of tricyclic antidepressants (imipramine and desipramine), an atypical antidepressant (nomifensine), known anorexic agents, haloperidol, and diazepam on food intake were compared in Sprague-Dawley rats over a 4-day test period. The tricyclic antidepressants produced decreases in food intake during the total 4-day test period following their administration. In contrast, the anorexic agents (d-amphetamine, cocaine, mazindol, fenfluramine and quipazine), nomifensine, and haloperidol produced decreases in food intake only on the day of their administration. Diazepam produced an increase in food intake only on the day of its administration. In addition to revealing that high doses of antidepressants can decrease food intake, this model appears to show some specificity for tricyclic antidepressants.     

Tyrosine administration decreases serum prolactin levels in chronically reserpinized rats

The injection of tyrosine, 200 mg/kg, decreased serum prolactin levels and elevated hypothalamic (and striatal) concentrations of two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, in chronically reserpinized rats. Tyrosine administration had none of these effects in otherwise untreated rats, and did not block the increase in serum prolactin that occurred 4 hours after a single injection of reserpine. As anticipated, the injection of dopa decreased serum prolactin in all rats. Valine, another large neutral amino acid, did not modify serum prolactin in chronically reserpinized animals. Since prolactin secretion is normally inhibited by dopamine released from the hypothalamus, reserpine treatment probably elevates serum prolactin by depleting the hypothalamus of dopamine. Our data suggest that tyrosine injection suppresses serum prolactin levels in chronically reserpinized rats by enhancing the synthesis and release of hypothalamic dopamine. Thus, administration of tyrosine, dopamine's dietary precursor, can alter physiologic functions that depend on dopamine.     

Effect on the administration of LHRH on LH and prolactin plasma levels in adult female rats ovariectomized and maintained in constant light (author's transl)]

The influence of prolonged periods of constant lighting on the plasma levels of LH and prolactin in adult female rats has been studied. No differences in either hormones are observed between intact animals under constant light of under a 12 hr (controls) darkness schedule. After ovariectomy LH values increase on both experimental conditions, with higher levels in the control group (p less than 0.01). After ovariectomy, a similar pattern is observed in animals under constant light, or under a 12 hr light darkness schedule, in the decrease of prolactin levels and in the increase of plasma LH levels after LHRH administration (100-1,000 ng). The stress induced by experimental manipulation, ether anesthesia and saline injection elevates plasma prolactin in both groups. LHRH administration blocks this response.     

Chronic treatment with a dopamine uptake blocker changes dopamine and acetylcholine but not glutamate and GABA concentrations in prefrontal cortex, striatum and nucleus accumbens of the awake rat

The present study was aimed to investigate the effects of a chronic treatment with the dopamine uptake blocker nomifensine on the in vivo extracellular concentrations of dopamine, acetylcholine, glutamate and GABA in the prefrontal cortex, striatum and nucleus accumbens. Male Wistar rats received intraperitoneal (i.p.) daily injections of nomifensine (10 mg/kg) or saline for 22 days. Microdialysis experiments were performed on days 1, 8, 15 and 22 of treatment to evaluate the effects of the injection of nomifensine or saline. Motor activity of the animals was monitored during microdialysis experiments. Injections of nomifensine increased extracellular concentration of dopamine in striatum and nucleus accumbens, but not in prefrontal cortex. Acetylcholine concentrations in striatum but not in nucleus accumbens were increased by nomifensine on days 15 and 22 of treatment. In prefrontal cortex, nomifensine increased acetylcholine levels without differences among days. No changes were found on glutamate and GABA concentrations in the three areas studied. Injections of nomifensine also increased spontaneous motor activity and stereotyped behaviour without differences among days. These results show that systemic chronic treatment with a dopamine uptake blocker produces differential effects on extracellular concentrations of dopamine and acetylcholine, but not glutamate and GABA, in different areas of the brain.     

Prostacyclin (PGI2) effects on anterior pituitary hormones in the rat in vivo.

Intravenous injection of 600 microgram PGE2 or PGI2 significantly increased serum LH and prolactin levels in estradiol treated ovariectomized rats. There was no effect on serum FSH concentration. PGE2 and PGI2 stimulated LH release in a non-dose dependent manner, while prolactin levels were positively correlated with the dose administered following PGI2 treatment. 6-keto-PGF1 alpha at a comparable dose had no effect on pituitary hormone levels. Subcutaneous administration of 1 mg/kg or 60 mg/kg PGI2 for seven days significantly depressed serum LH level both in male and female rats. These doses had no effect on serum FSH or prolactin levels.     

An immunoradiometric assay for squirrel monkey prolactin.

Determination of immunoreactive prolactin in squirrel monkeys has been hampered by the lack of specific antibodies. We investigated the adaptability of a commercially available immunoradiometric assay for human prolactin, which employs two separate monoclonal antibodies (MAb I and II) to human prolactin, to determine the presence of squirrel monkey prolactin. We found that immunoreactivity curves for prolactin in squirrel monkey pituitary homogenates and serum were parallel to human prolactin standards, suggesting that the epitopes recognized by these antibodies were common to both human and squirrel monkey prolactin. Both nonglycosylated (23 kD) and glycosylated (26 kD) forms of squirrel monkey prolactin were detected in squirrel monkey pituitary homogenates by Western blot analysis using [125I]-MAb II. Neither sheep nor rat prolactin was recognized by Western blot analysis, indicating that the assay may be specific for primate prolactins. We examined the effect of ketamine HCl, an anesthetic that has been shown to elevate serum prolactin levels in other primates, on prolactin secretion in squirrel monkeys. Serum prolactin levels increased greater than fourfold after the administration of ketamine HCl (30 mg/kg b.w., i.m.) compared with control levels. Serum prolactin levels were unaffected by anesthesia with pentobarbital sodium (15 mg/kg b.w., i.v.). This assay provides a reliable and sensitive method for determining immunoreactive squirrel monkey prolactin.