Evaluation of dopaminergic tone in postmenopausal women: effects of piribedil on anterior pituitary hormones.

In order to evaluate the relationships between gonadal steroid hormones and central dopaminergic (DA) tone, we have administered a "weak" dopamine agonist drug (piribedil) in 12 normal women, who were postmenopausal for at least 5 yrs, and we have studied the effects on anterior pituitary hormone release. We observed a decrease of plasma PRL levels and an increase of plasma GH values with all doses (40, 60, 100 mg p.o.) of the drug employed. No consistent changes in plasma FSH, LH, ACTH and TSH were observed and no side effects were reported. These results were greatly different from those previously described in premenopausal women in whom dose-related effects were observed and were similar to those observed in normal male subjects. The differences in the response to piribedil observed in women before and after the menopause could be due to a different sexual steroid environment.     

Effects of a dopaminergic stimulant,amfonelic acid,on anterior pituitary hormone release in conscious rats

The response of plasma LH, Prolactin, GH and TSH levels to systematic administration of a specific central dopaminergic stimulant, amfonelic acid (AFA), by intravenous pulse injection in ovariectomized (OVX) and OVX estrogen-progesterone primed conscious rats has been evaluated. Intravenous injection of 0.2 mg/kg of AFA had no influence on plasma LH concentration until 60 min after injection when it was significantly elevated. Increasing the dose to 1 mg/kg reduced LH titers at 15 and 30 min with a return to preinjection levels by 60 min. AFA produced a dose-dependent decrease in plasma prolactin levels; the decrease occurred as early as 5 min after injection. AFA, both at 0.2 and 1 mg/kg doses, was effective in producing a sharp, dose-related rise in plasma GH levels. By contrast, TSH levels were significantly suppressed by both doses of AFA. Injection of the 1 mg/kg dose of AFA did not modify plasma LH levels in OVX-steroid-primed animals, white producing a comparable effect on plasma prolactin, GH and TSH levels to that observed in OVX animals. The present results indicate that endogenously released DA can have profound effects on pituitary hormone release, inhibiting PRL and TSH discharge, stimulating GH release and either inhibiting or stimulating LH release.     

The lack of effect of bupropion HCL (Wellbatrin) on the secretion of growth hormone and prolactin in humans

The effect of bupropion HCL (Wellbatrin), a new anti-depressant, on the secretion of GH and PRL in healthy male subjects and male hyperprolactinaemic patients was studied. The study was a randomised double-blind test in which 6 subjects and 6 patients who had been treated with neuroleptics were each, in accordance with the random plan, treated once with placebo and once with 200 mg bupropion p.o.. After administration of the test substance, blood was drawn to measure bupropion, GH and PRL up to 240 minutes thereafter. Neither in the healthy men nor in the patients could a specific effect of bupropion on the secretion of GH be shown in comparison to placebo although bupropion in all subjects and patients was well reabsorbed. As opposed to the results of Stern et al. (5), no change in the secretion of PRL was measured in either the healthy subjects or the hyperprolactinaemic patients. In addition, no change in the TRH-induced stimulation of PRL could be measured. The results of the present study offer no positive contribution towards an explanation of the mechanism of bupropion.     

Possible dopaminergic system involvement in LH and PRL responses to naltrexone treatment

Naltrexone (Nalt) causes a rapid increase in luteinizing hormone (LH) level. This short term increase of LH concentration declines to baseline levels in less than 1 hour. Addition of pimozide (0.1 mg) caused a blunted response to Nalt challenge, with significantly reduced LH peak values compared with Nalt treatment alone. Pimozide alone caused a delayed decrease compared with baseline LH values. By following plasma prolactin (PRL) levels it was shown that pimozide administration increased PRL levels rapidly for more than 2 hours. Addition of Nalt to pimozide-treated rats significantly decreased plasma PRL values compared with pimozide alone. Nalt injected by itself attenuated PRL baseline levels. Thus, the mechanism by which pimozide caused PRL elevated level is via the dopaminergic as well as the opioid system. It is suggested that the opioid system controls plasma PRL and LH levels through other hypothalamic neurotransmitters in addition to dopamine.     

Effect of experimentally induced hyperprolactinemia on growth hormone secretion

In order to study the existence of possible interrelation-ships between prolactin (PRL) and growth hormone (GH) secretions, adult male rats bearing an anterior pituitary graft under the kidney capsule since day 90 of life and their sham-operated controls were submitted to a single i.p. administration of L-dopa (50 mg/kg weight) or saline 30 days after the operation. Plasma PRL and GH levels were measured by using specific RIA methods. Dopamine (DA) and norepinephrine (NE) contents in the hypothalamus and in the in situ anterior pituitary gland were measured by using a specific radioenzymatic assay. An increase in plasma PRL levels and a decrease in plasma GH levels were shown in grafted rats. Hypothalamic contents of DA and NE were increased in these animals, while the anterior pituitary content of DA was not modified as compared to controls. The administration of a single injection of L-dopa led to decreases of plasma PRL and GH levels in both grafted and control rats, but while marked increases in hypothalamic and anterior pituitary contents of DA were shown in both groups, the hypothalamic content of NE was only increased in control animals. These data suggest that PRL and GH secretions were closely related. Dopamine could be mediating the action of PRL on GH, while NE would be less involved.     

Prolactin lowering effect of amphetamine in normoprolactinemic subjects and in physiological and pathological hyperprolactinemia

The effect on plasma prolactin (PRL) of d-amphetamine (Amph) was studied in normo- and hyperprolactinemic subjects. In normoprolactinemic women Amph failed to lower plasma PRL levels when infused intravenously over 1 h at the dose of 7.5 mg, but induced at the dose of 15.0 mg a modest inhibition of plasma PRL (maximum PRL inhibition 20 +/- 4.5% at 45 min). Likewise, in puerperal women Amph at the dose of 7.5 mg did not decrease significantly plasma PRL levels but it was active in this respect (maximum inhibition 37 +/- 10% at 120 min) at the dose of 15.0 mg. In subjects with presumptive evidence of a PRL-secreting adenoma, Amph at either the 7.5 mg or the 15.0 mg dose failed to alter baseline PRL levels. These results indicate that Amph is a poor PRL suppressor in either normo- or hyperprolactinemic subjects. It is proposed that this may be due to the drug's ability to effect release of dopamine mainly from a non-granular pool of the amine.     

Circadian variations in plasma growth hormone and prolactin in the infant rat: Comparison with the adult pattern

Radioimmunoassayable (RIA) plasma growth hormone (GH) and prolactin (PRL) levels were determined at 3 hr intervals during a controlled 24-hr light-dark cycle in 10-day-old male and female rats; parallel measurements were made of brain monoamines (MA's), dopamine (DA), norepinephrine (NE) and serotonin (5-HT) concentration. Plasma GH and PRL and brain MA levels found in infant rats were compared to the same determinations made during the 24-hr cycle in 50-day-old male rats. GH levels were rather uniform and did not show circadian periodicity in the plasma of infant rats, while PRL levels showed a diurnal surge in the late afternoon hr (1800). In adult rats, GH levels exhibited wide fluctuations during the 24-hr cycle and no circadian periodicity, while PRL levels showed one diurnal (1500–1800) and one nocturnal (2400) surge. A pulsatile GH secretion was found in adult rats sampled at 15 min intervals over a period of 2 hr, which seemed to be lacking in infant rats. In the brain of infant rats, DA and NE levels exhibited circadian patterns which resembled the ones present in the brain of adult rats, whereas no circadian variations were present in 5-HT levels.     

Calcitonin inhibition of physiological and stimulated prolactin secretion in rats

The administration of salmon Calcitonin (sCT) intravenously (2.5 or 10 μg/kg) or into the lateral cerebral ventricles (2.5 or 25 ng/rat, i.c.v.) of unanaestized male rats induced clearcut decreases in plasma prolactin(PRL) levels. The i.c.v. injection of one of these doses of sCT (25 ng/rat) into rats with median eminence lesions was completely ineffective, while it induced a dramatic decrease in plasma PRL levels of sham-operated rats. Morphine- and heat stress-stimulated PRL levels were also abolished by sCT injection (250 ng/rat i.c.v.). The sCT-induced decrease in PRL levels was completely overcome by haloperidol, a dopamine-receptor blocker. We conclude that sCT may affect PRL secretion via an hypothalamic system, probably involving dopaminergic neurons. The present results indicate that CT, like many others peptides, may affect PRL secretion, directly or indirectly, even though further research is necessary to determine whether this effect has pharmacological or physiological importance.     

Inhibition of pituitary bioactive prolactin secretion in the male rat by the glucocorticoid agonist decadron phosphate.

In the present studies, the soluble glucocorticoid agonist, decadron phosphate (DEC), was administered i.v. to intact adult male rats in order to evaluate the effects of glucocorticoid receptor stimulation on circulating levels of immunoreactive (ir-) and bioactive (bio-) prolactin (PRL). In light of reports that glucocorticoid-specific receptors exist within the rat brain, additional experiments investigated the effects of intracerebroventricular (i.c.v.) administration of graded doses of the same drug on pituitary ir- and bioPRL secretion. Concentrations of ir- and bioPRL in samples obtained before and after drug treatments were determined by standard PRL radioimmunoassay and the Nb2 rat node lymphoma bioassay, respectively. Rats injected i.v. with 0.5 mg DEC/kg body weight, but not those treated with a tenfold lesser dose, exhibited decreased plasma irPRL concentrations. However, both doses promoted a decline in circulating levels of bioPRL compared to vehicle-treated controls, along with an overall reduction in the plasma bio/irPRL ratio. The magnitude and duration of this drug-induced decline in biopotency of secreted hormone was dose-dependent. While the plasma bio/irPRL ratio was diminished only transiently in rats injected with 0.05 mg DEC/kg, treatment with the higher dose led to a sustained decrease in the plasma bio/irPRL ratio for the duration of the experiment. The current studies also show that intracerebral administration of DEC resulted in dose-dependent alterations in pituitary PRL release. Circulating levels of ir- and bioPRL were not altered in rats injected i.c.v. with 10 ng of DEC, the lowest dose tested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal effects of CV 205-502, a novel octahydrobenzo [g] quinoline with potent dopamine agonist properties

Following the success of ergot alkaloids and their synthetic derivatives in treating a variety of pathophysiological disturbances, efforts have been concentrated on the synthesis of new derivatives and partial structures with the aim of dissecting out a specifically dopaminomimetic pharmacophore. Accordingly CV 205-502, a structure which superposes the linear benzo [g] quinoline segment of apomorphine on the substituted pyrrolo [3,4- g] quinoline moiety of the ergolines was designed. This study was performed in normal young volunteers to investigate the effect of single oral doses of CV 205-502 on plasma prolactin levels and on other endocrine parameters (GH, LH, FSH, TSH and cortisol) as well as on tolerability. 10 volunteers participated in a dose-ranging study. They received single oral doses of 0.01 to 0.09 mg CV 205-502, in order to assess the prolactin suppressant action. 6 volunteers were given a dose of 0.06 mg CV 205-502 in order to determine the endocrine profile of the compound. The duration of action of 0.06 mg CV 205-502 was investigated in 6 subjects by measuring plasma PRL and GH levels for 48 h. The results show strong dose-dependent suppression of PRL appearing following doses between 0.04 and 0.09 mg of CV 205-502. PRL was markedly suppressed for more than 24h. and the peaks of the normal sleep profile were abolished. Intermittent transient GH increases occurred during the first 6 hours; sleep profiles were normal. Compared with placebo values, no changes were seen in the levels of any other hormone except TSH, which decreased. Tolerability was good and no drug attributable changes in safety measures occurred. This study demonstrates that CV 205-502 is a potent and long acting PRL suppressant compound and suggest that this novel octahydrobenzo [g] quinoline will prove to be a therapeutically useful dopaminomimetic compound.     

Pharmacological activation of the GABAergic system does not affect GH and PRL release in acromegaly

An extensive hypothalamic neurotransmitter impairment has been proposed in acromegaly. However, at the moment, the hypothalamic GABAergic system has been little investigated in this disorder. Since GABA has been shown to modulate growth hormone (GH) and prolactin (PRL) secretion in human subjects, it seemed reasonable to investigate hypothalamic GABAergic functioning through the assessment of basal GH and PRL responses to pharmacological activation of this system. 800 mg of sodium valproate (SV), a drug with GABA facilitating properties, were administered orally to 7 acromegalic patients and 9 healthy volunteers. Blood samples were collected before and after the drug administration for the measurement of plasma GH and PRL levels. SV induced a clear-cut rise in basal GH and a decrease in basal PRL in healthy subjects, but it did not induce any change in the basal levels of these hormones in acromegalics. These results suggest that the response of GH and PRL to SV in acromegaly is qualitatively different from normal controls.     

The conditioned place preference paradigm in rats: effect of bupropion

The effect of bupropion in the conditioned place preference paradigm in rats is described. In doses between 10 and 50 mg/kg i.p. bupropion increased the time rats spent in a shuttle box compartment conditioned to this compound. This effect of bupropion was not blocked by pretreatment of the animals with 0.1 mg/kg i.p. haloperidol or 50 mg/kg i.p. sulpiride. The same doses of the neuroleptics did, however, attenuate locomotor hyperactivity induced by bupropion. Bupropion thus seems to belong to the group of CNS stimulants whose effect in the conditioned place preference paradigm is not blocked by neuroleptics.     

Venlafaxine enhances the effect of bupropion on extracellular dopamine in rat frontal cortex

Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co-administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA.     

Effects of clofibrate on plasma tryptophan, growth hormone, and prolactin and on brain tryptophan and serotonin in prepubertal rats

The effects of clofibrate administration (200 mg/kg, po) on somatic growth, plasma levels of lipids, tryptophan, growth hormone (GH), and prolactin (PRL), as well as on brain concentrations of tryptophan and 5-hydroxytryptamine (5-HT) were studied in prepubertal male rats. The drug did not significantly alter ponderal growth, but an appreciable reduction of tail length was observed in rats treated for 30 days. Triglyceride concentrations in plasma showed a 43% diminution after 30 days of treatment, whereas free fatty acid (FFA) levels were not modified. Clofibrate administration for 7, 15, or 30 days caused a fall in total tryptophan and a significant increase of the free fraction in plasma with no change in brain tryptophan levels. Brain 5-HT was generally unaffected but a marked elevation of this parameter was noted in rats treated for 15 days. Plasma GH and PRL concentrations remained unaltered. It may be concluded from these findings that the slight reduction of somatic growth, the diminution of triglycerides, and the increase of free tryptophan in plasma, induced by chronic clofibrate treatment, are not associated with variations in brain tryptophan and 5-HT levels or with modifications of plasma GH and PRL titers.     

Rat Strain Differences in Responses of Plasma Prolactin and PRL mRNA Expression After Acute Amphetamine Treatment or Restraint Stress

1. The aim of this study was to compare the effects of acute amphetamine (AMPH) treatment and restraint stress on plasma level of prolactin (PRL) and PRL mRNA expression in the adenohypophysis in Sprague–Dawley and Lewis male rats, the latter known to have a deficient hypothalamo–pituitary-adrenal (HPA) axis.2. Both restraint stress and AMPH treatment (i.p. in a dose of 8 mg/kg of b.w.) were applied 15 or 30 min before termination of the experiment. Plasma PRL and corticosterone (CORT) were determined by radioimmunoassay. PRL mRNA expression was estimated by a dot-blot hybridization.3. Restraint stress and AMPH treatment induced a significant increase in theCORT plasma level, as an indicator of stress response. Compared to Sprague–Dawley rats, the magnitude of CORT increase after both stimuli was significantly lower in Lewis rats.4. Although restraint stress significantly increased the PRL plasma levels in both rat strains, AMPH treatment reduced the PRL levels in both rat strains. However, the changes of PRL plasma levels had another pattern in Lewis rats than in Sprague–Dawley rats. Control plasma PRL levels were significantly higher in Lewis rats, and in this rat strain AMPH treatment for 30 min increased the PRL levels as compared to the values obtained after AMPH treatment for 15 min.5. Expression of PRL mRNA in adenohypophysis by restraint stress and AMPH treatment had a similar pattern. After a 15-min lasting restraint stress, the expression of PRL mRNA was decreased insignificantly in both rat strains. AMPH treatment induced in Sprague–Dawley rats a significant decrease of PRL mRNA after a 15-min interval while after 30 min there was a significant increase. However, in Lewis rats AMPH failed to significantly change PRL mRNA.6. The results from the present study indicate that the mechanisms mediatingthe effects of acute restraint stress and acute AMPH treatment differ in PRL response in Sprague–Dawley and Lewis male rat strains. Differences in the observed responses in Lewis rats could be related to the deficient activity of HPA axis in this rat strain.     

Mechanism of the effect of urethane on the secretion of prolactin in the male rat

A subcutaneous injection of urethane (200 mg/100 g body wt.) into adult male rats resulted in a significant increase in serum prolactin (PRL) at 30 minutes. Subsequent measurements at 60, 90 and 120 minutes postinjection revealed a marked and rapid decrease in serum PRL to levels significantly lower than those of unanesthetized animals. The administration of the dopamine antagonist pimozide (8, 40 or 200 μg) 30 minutes after urethane injection elevated serum PRL levels in a dose-dependent manner and thus prevented the urethane-induced depression in serum PRL observed at 60 minutes postinjection. Hypothalamic synthesis of ¹⁴C-dopamine from its precursor ¹⁴C-tyrosine was measured in both urethane-anesthetized and unanesthetized rats. The synthesis of hypothalamic dopamine was dramatically increased in the urethane-anesthetized animals as compared to newly synthesized hypothalamic dopamine levels in the unanesthetized controls. These results indicate that the PRL-inhibitory effects of urethane anesthesia in the rat may be exerted through increased dopaminergic activity.     

生长激素和催乳素放射免疫测定法的建立与应用

目的：建立测定大鼠垂体和血浆中生长激素（GH）和催乳素（PRL）含量的高特异性、高灵敏度的双抗放射免疫测定（RIA）法;研究急性低氧对垂体激素GH和PRL的作用。方法：用氯胺－T法进行抗原放射性碘标记;采用平衡饱和加样程序的双抗RIA法测定。结果：用该方法测定急性低氧（0．5h）时血浆和垂体GH和PRL含量,7km低氧,垂体GH含量明显升高（P＜0．05）,血浆则相反;7km低氧,明显降低垂体和血浆PRL含量（P＜0．01）;而5km低氧对GH和PRL的作用与对照组比无统计学差异。结论：本双抗RIA法具有高特异性、高灵敏度及简便易行等特性;用该法测定提示急性低氧可抑制大鼠GH和PRL的分泌。     

Long-term bromocriptine therapy and predictive tests in acromegaly

The value of predictive tests in bromocriptine therapy and the effects of long-term bromocriptine therapy were investigated in acromegalic patients. In 72 acromegalic patients, there was a tendency for patients with a plasma GH response to TRH or with an elevated basal plasma PRL level, but without a plasma GH response to LHRH, to have a plasma GH response to bromocriptine, though statistical analysis did not reveal a significant difference. Acute and chronic effects of bromocriptine were significantly interrelated, while the chronic effect of bromocriptine and abnormal plasma GH response to TRH or elevated plasma PRL levels were not, in 18 acromegalic patients. These results suggest that the acute bromocriptine test is a better predictor than the TRH test and plasma PRL levels for evaluating the effects of chronic bromocriptine therapy. To maintain the low plasma GH levels, increasing doses of bromocriptine were needed in most patients, and failure to control the elevated GH level despite increasing doses was observed in 2 of 18 patients.     

Inhibitory effects of somatostatin analogs on prolactin secretion in rats pretreated with estrogen or haloperidol

The effect on prolactin (PRL) secretion of acute administration of new octapeptide analogs of somatostatin (SS) with an enhanced and prolonged growth hormone inhibitory activity was investigated in rats under various pretreatment conditions with estrogen and antidopaminergic drugs. Analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), at a dose of 5 micrograms/100 g body wt, did not decrease basal PRL levels in thiopental-anesthetized female rats, untreated or treated with estrogen benzoate (EB) (8 micrograms/rat) for 5 days. When haloperidol was used to elevate PRL level, a single injection of RC-121 inhibited PRL release in EB-pretreated female rats or untreated female and male rats. Analog D-Phe-Cys-Trp-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), which has a potency similar to RC-121 in the tests on inhibition of GH, in a dose of 0.2 microgram/100 g body wt, did not lower the elevated PRL level induced by alpha-methyl-p-tyrosine and/or pretreatment with EB (100 micrograms/rat, 3 and 6 days before) in pentobarbital-anesthetized male rats. However, both analogs RC-121 and RC-160, in doses of 0.2 microgram/100 g body wt, decreased the PRL levels elevated by prolonged pretreatment with EB (100 micrograms/rat, twice a week for 3 weeks) in male rats. These results indicate that acute administration of these SS analogs can induce a prolonged inhibition of PRL release when PRL is acutely elevated by haloperidol or chronically elevated by 3 weeks of estrogen administration. Future additional studies are required to investigate the effects of chronic administration of these SS analogs on PRL levels.     

Discrepancy between prolactin (PRL) messenger ribonucleic acid and PRL content in rat fetal pituitary cells: possible role of dopamine

Data are controversial concerning the time when PRL-synthesizing cells are detected for the first time in the rat pituitary. Using a very sensitive immunocytochemical technique, we could visualize only a few PRL cells before day 10 after birth. At that time, pituitary PRL was still 200 times less abundant than in the adult (on a tissue weight basis) whereas PRL mRNA per mg total RNA was only 80 times lower than in the adult. However, by in situ hybridization, we could demonstrate the presence of PRL mRNA in cells from fetal day 18 on. We have also followed the expression of GH gene in rat pituitary cells during development. In contrast to results obtained with PRL cells, quantitative analysis of cDNA probe hybridization to GH mRNA correlated well with measurements of immunostained cells. We found that PRL was released in the blood from fetal day 19 onwards. Thus, at that time PRL is synthesized and secreted but not stored. We therefore measured brain dopamine levels, and the data support the idea that the rise in dopamine levels after birth contributes to PRL storage. We confirmed in vitro that newborn pituitary cells can store PRL when cultured in the presence of dopamine.