The neuroendocrinological profile of roxindole,a dopamine autoreceptor agonist,in schizophrenic patients

Roxindole is a potent autoreceptor-selective dopamine agonist with additional properties as a serotonin reuptake inhibitor and 5-HT_1A agonist. In order to get more insight into its mode of action in various psychiatric populations, we evaluated the effects of subchronic roxindole treatment on pituitary and adrenal hormone secretion, i.e. release of prolactin, thyroid stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), and cortisol. Fifteen schizophrenic patients with positive and negative symptomatology, respectively, were treated with roxindole for 28 days. Both basal and thyrotropin releasing hormone (TRH) -induced prolactin secretion diminished significantly to 26.4% and 22.8% of baseline levels, respectively, under roxindole. Basal GH secretion was insignificantly elevated by 89%, whereas GH levels increased nearly 3-fold after stimulation by TRH. TSH levels decreased insignificantly to 57.5% of baseline levels, while TRH-induced TSH release was not affected by subchronic roxindole. Roxindole treatment influenced neither LH secretion nor cortisol release. Our results indicate that roxindole's dopaminergic actions might prevail over its serotonergic effects, at least as far as the regulation of anterior pituitary hormone secretion is concerned.     

Ca2+ channel agonists enhance thyrotropin-releasing hormone-induced inositol phosphates and prolactin secretion.

The dihydropyridine Ca2+ channel activator BAY K 8644 (1 microM) stimulated basal prolactin secretion from perifused primary cultures of anterior pituitary cells and potentiated the stimulation of prolactin secretion by 1 microM thyrotropin-releasing hormone (TRH) 5-fold over 30 min. This potentiation was mimicked by other dihydropyridine agonists CGP 28392 and (+)-SDZ 202-791 and by (-)-BAY K 8644 (1 microM), but not by (+)-BAY K 8644. The Ca2+ channel antagonist nimodipine, at a concentration sufficient to block BAY K 8644-stimulated 45Ca2+ uptake in GH4C1 anterior pituitary tumor cells, decreased basal prolactin secretion and blocked the enhancement of basal and TRH-stimulated secretion by BAY K 8644. These results suggest that dihydropyridine agonists potentiate TRH-induced secretion through interaction with known stereospecific sites on Ca2+ channels. In GH4C1 cells, BAY K 8644 alone did not affect inositol polyphosphate accumulation, but potentiated TRH-stimulated accumulation of inositol 1,3,4-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Accumulation of the Ca(2+)-mobilizing isomer inositol 1,4,5-trisphosphate was not potentiated, suggesting that potentiation of TRH-stimulated hormone secretion by BAY K 8644 does not result from synergistic stimulation of phospholipase C, but may correlate with enhanced inositol trisphosphate-3-kinase activity.     

Effects of selective histamine H3-receptor ligands on prolactin and growth hormone secretion in the rat.

The effects of intracarotid (i.a.) administration of the histamine (HA) H3-receptor agonist (R)-alpha-methyl-histamine (alpha MeHA) and of the H3-antagonist thioperamide, (THIO) on basal or morphine (M)-induced prolactin (PRL) and growth hormone (GH) secretion were studied in male rats. M was administered 3 h after the H3-drugs. Neither THIO (2.5 mg/kg) nor alpha MeHA (10 mg/kg) changed basal PRL levels and only THIO enhanced the PRL-releasing effect of M (6 mg/kg). Basal GH secretion was not modified by THIO. alpha MeHA slightly increased GH secretion. THIO significantly decreased M-stimulated GH secretion (1 mg/kg, i.a.) and alpha MeHA slightly increased it. These results, in agreement with previous evidence obtained after central HA administration, indicated that endogenous brain HA facilitates PRL and inhibits GH secretion.     

Phorbol esters affect pituitary growth hormone (GH) and prolactin release: the interaction with GH releasing factor, somatostatin and bromocriptine

Phorbol esters are tumor promotors that directly stimulate protein kinase C activity. We asked whether these agents affect basal or receptor initiated alterations in growth hormone (GH) and prolactin release. In 4 h incubations of anterior pituitary cells, phorbol esters enhanced basal and GH releasing factor (GRF)-induced GH release. Somatostatin reduced by 38% the 4-fold stimulation of GH release induced by phorbol ester. These tumor promoters also reversed the ability of bromocriptine, a dopamine agonist, to inhibit prolactin release, with no apparent effect on basal prolactin secretion. When these agents were applied for 24 h, an increase in the basal release of both GH and prolactin was apparent. These data lead us to suggest that an intact protein kinase C system may be necessary for the full expression of GRF-stimulated GH release and dopaminergic inhibition of prolactin release.     

Bimodal action of [Asu1,7]eel-calcitonin on phosphoinositide hydrolysis in cultured anterior pituitary cells.

[Asu1,7]Eel-calcitonin, a semisynthetic analog of eel-calcitonin displaying high stability and full biological activity, was used to study the effect of calcitonin on phosphoinositide turnover in cultured anterior pituitary cells. Incubation of cells with [Asu1,7]eel-calcitonin produced a slight, concentration-dependent increase in [3H]inositol monophosphate accumulation, without modifying thyrotropin-releasing hormone (TRH)-stimulated phosphoinositide hydrolysis. This effect was correlated with a stimulatory action on prolactin secretion. Conversely, a long-term preincubation with [Asu1,7]eel-calcitonin reduced basal as well as TRH-induced [3H]inositol monophosphate formation. This effect was concentration-dependent, was not due to an increase of cyclic AMP intracellular levels, and was attenuated in the presence of maximally effective concentrations of TRH. Such a long incubation in the presence of [Asu1,7]eel-calcitonin resulted in a marked inhibition of prolactin secretion. The present data confirm and extend previous findings showing an interference of calcitonin with the intracellular cascade consequent to membrane phospholipase C activation and further support a role for calcitonin in the modulation of hormone secretion at the pituitary.     

Interactions of nicotine and pentobarbitone in the regulation of telencephalic and hypothalamic catecholamine levels and turnover and of adenohypophyseal hormone secretion in the normal male rat

Summary The effects of single intraperitoneal injections of nicotine (1 mg/kg) and the sedative-hypnotic drug pentobarbitone (30 mg/kg) alone or in combination have been studied on catecholamine (CA) nerve terminal system of the hypothalamus and the forebrain and on the adenohypophyseal hormone secretion of the normal male rat.Nicotine produced discrete reductions of dopamine (DA) levels and increases of DA turnover in striatal and limbic areas of the forebrain and increases of amine turnover in different hypothalamic noradrenaline (NA) nerve terminal systems. These effects were all antagonized by simultaneous treatment with pentobarbitone. Pentobarbitone alone, however, did not modulate CA levels or turnover in the various parts of the hypothalamus and forebrain analyzed. On the other hand, pentobarbitone increased GH and prolactin secretion and in association with tyrosine hydroxylase inhibition markedly reduced corticosterone secretion. These effects were partly counteracted by nicotine in the case of GH and prolactin secretion. Furthermore, a positive interaction appears to exist between nicotine and pentobarbitone in their actions on LH secretion.The results suggest that pentobarbitone can antagonize the actions of nicotine on CA levels and turnover in various CA nerve terminal systems of the brain leading to possible reductions in nicotine induced arousal and positive reinforcement. The neuroendocrine actions of pentobarbitone do not seem to be greatly modulated through nicotinic cholinergic receptors.     

Effects of methyldopa on prolactin and growth hormone.

The effects of administration of methyldopa on serum prolactin and growth hormone (GH) concentrations in hypertensive patients were studied. Single doses of methyldopa (750 or 1000 mg) significantly increased serum prolactin levels, peak concentrations occurring four to six hours after drug administrations. Long-term methyldopa treatment was associated with threefold to fourfold increases in basal prolactin levels compared with those in normal subjects. In patients treated with methyldopa for two to three weeks the GH response to insulin hypoglycaemia was significantly greater than in normal subjects and untreated hypertensive patients. In contrast, patients treated for prolonged periods (mean 13-4 months) had a GH reponse indistinguishable from normal.     

Pituitary secretion after administration of a new cerebroactive drug, fipexide.

The effect of a single oral dose of 400 mg fipexide on pituitary secretion was investigated in 10 elderly non-endocrine patients. Fipexide induced significant decrease (P less than 0.05) in serum prolactin (PRL) values at 90 and 120 min after drug administration, without affecting serum growth hormone (GH), gonadotropin (LH and FSH), thyrotropin (TSH) and cortisol values. Fipexide was unable to modify metoclopramide-induced PRL release in five of these patients. Our results show that this drug acts as a mild dopamine (DA) agonist, probably not directly affecting hypothalamic and/or pituitary DA receptors but indirectly via a reduced DA re-uptake at the pre-synaptic level.     

Changes in sleep electroencephalogram and nocturnal hormone secretion after administration of the antidyskinetic agent sarizotan in healthy young male volunteers

Rationale Sarizotan is a 5-HT_1A agonist with high affinity to D₃ and D₄ receptors. In animal experiments, the drug shows a strong anti-cataleptic effect and suppresses effectively dyskinesias in animal models of l-dopa-induced dyskinesia and of tardive dyskinesia. Data from an open pilot study in patients with Parkinsons disease show clear indication of a treatment effect against l-dopa-induced dyskinesia.Objective CNS-active drugs are known to modulate sleep electroencephalogram (EEG) and sleep-related hormone secretion. 5-HT_1A agonists suppress rapid-eye movement (REM) sleep and enhance the secretion of ACTH, cortisol, prolactin and growth hormone (GH) at daytime. We hypothesised that sarizotan shares these effects. Furthermore, we were interested in the influence of sarizotan on leptin, which participates in the regulation of the energy balance and is enhanced after various psychoactive drugs.Methods Ten healthy male subjects were investigated twice in a double-blind, placebo-controlled crossover design. Sleep EEG and nocturnal hormone secretion of ACTH, cortisol, prolactin, GH and leptin were examined after oral administration of either placebo or 20 mg of sarizotan at night.Results After administration of sarizotan, a significant reduction of REM sleep and total sleep time in conventional sleep EEG and a significant reduction of sigma- and theta-power in spectral analysis were observed. The main effect on nocturnal hormone secretion was a significant elevation of prolactin and of ACTH in the first half of the night.Conclusions While REM sleep was suppressed, the endocrine effects of 20 mg sarizotan at night were weak. Its sleep-endocrine profile is comparable to the effects provoked by selective 5-HT reuptake inhibitors.     

Synthetic human growth hormone releasing factor (h-GRF-I-44-NH2) dose response effect on growth hormone and prolactin secretion in healthy adult men

Summary The dose-effect relationship of an i.v. bolus of synthetic h-GRF-44 on growth-hormone and prolactin secretion has been studied. Seven healthy adult volunteers received in a random order h-GRF-44 2.5, 5, 10, 20, 40 and 80 µg and a placebo. Plasma growth hormone (GH) was determined between 30 min before and 240 min after injection, the area under the curve (AUC) and the peak GH level being used to assess the response. For both parameters a dose-effect relationship was observed. Doses as low as 2.5 µg were capable of eliciting a rise in GH plasma levels in few patients. Above 40 µg the dose-effect curves tended to plateau, although the decrease in the slope of the dose-effect curve at the peak was more marked. Intersubject variability was large, so precise determination of the minimal effective dose as well as the lowest dose giving a maximal effect was not possible. The available evidence suggests that the i.v. dose of synthetic h-GRF-44 (SR 95228) which is likely to promote GH release into the blood stream in most healthy adults is within the range 40–100 µg. In these healthy adults unwanted effects were infrequent with these low doses. Unlike previous experience with higher doses of another synthetic h-GRF-44, prolactin secretion in this study was not affected.     

Inhibitory action of methadone and its metabolites on erg-mediated K+ current in GH₃ pituitary tumor cells

Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemia. The mechanism of how Mtd induces prolactin secretion remains unclear. The effects of Mtd and its two main metabolites (EDDP: (±)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium percholarate and EMDP: 2-ethyl-5-methyl-3,3-dipnehyl-1-pyrroline) on ion currents were investigated in GH? pituitary tumor cells. Hyperpolarization-elicited K+ currents in GH? cells bathed in a high-K(+), Ca(2+)-free solution were studied to evaluate the effects of Mtd and other related compounds on the ether-à-go-go-related-gene (erg) K(+) current (I(K(erg))). Mtd suppressed the amplitude of I(K(erg)) in a concentration-dependent manner with an IC(50) value of 10.4 μM. With the aid of a minimal binding scheme, the inhibitory action of Mtd on I(K(erg)) was estimated with a dissociation constant of 8.2 μM. Mtd tended to increase the rate of I(K(erg)) deactivation in a voltage-dependent fashion. EDDP (10 μM) had no effect on I(K(erg)), while EMDP (10μM) slightly suppressed it. In GH? cells incubated with naloxone (30 μM), the Mtd-induced inhibition of I(K(erg)) remained unaltered. Under cell-attached voltage-clamp recordings, Mtd increased the frequency of spontaneous action currents with no change in current amplitude. Similarly, Mtd can suppress I(K(erg)) in differentiated NG108-15 cells; dynorphin A(1-13) did not reverse Mtd-induced inhibition of I(K(erg)). This study shows that Mtd has a depressant effect on I(K(erg)), and suggests its ability to affect membrane excitability and prolactin secretion. The cyclization of Mtd, in which EDDP and EMDP are formed, tends to be critical in removal of the Mtd binding to erg K+ channel.     

Narcotic analgesics and endorphins and the release of pituitary hormones (author's transl)

This report concerns a review of the neuroendocrine effects of narcotic analgesics and endorphins. Acute administration of narcotic analgesics to rats increases the blood levels of ACTH, GH and prolactin, and decreases levels of LH and TSH, however, there is no general consensus regarding changes in serum FSH, ADH and oxytocin as induced by narcotics in rats. In humans, the narcotic analgesic increases in serum prolactin, decreases in serum LH and has no effect on the release of other known pituitary hormones. Endorphins mimic morphine regarding hormonal effects. Effects of naloxone on the basal levels of prolactin, LH or GH were inverse to the effects seen with narcotics and endorphins, therefore endorphins may play a role in regulating the basal levels of these hormones. Narcotics analgesics depress the increased blood levels of prolactin, gonadotropins or TSH elicited by specific measures. While chronic administration of morphine results in tolerance to the stimulant effect of ACTH, and possibly of prolactin secretion, tolerance does not develop to the stimulant effect on GH secretion. The analgesic potency of narcotic analgesics correlates with their suppressive effect on the pituitary-gonadal system and the potency with which endorphins bind to the opiate receptors correlates with their prolactin releasing activity. It is assumed that narcotic analgesics and endorphins exert their hormonal effects by altering the release of neurotransmitters in the CNS. Thus, a release of hypothalamic releasing hormones is involved rather than a direct action on the pituitary. The central neurotransmitter systems involved in the hormonal effects of narcotics are now being intensively investigated by various groups of workers.     

Growth hormone, insulin, and prolactin secretion in anorexia nervosa and obesity during bromocriptine treatment

We studied secretion of growth hormone (GH), insulin, and prolactin in eight women with anorexia nervosa and nine women with refractory obesity before and during treatment with bromocriptine, 10 mg/day. In the anorexic patients the raised plasma GH concentrations occurring during an oral glucose tolerance test fell significantly while on bromocriptine treatment, but there was no change in plasma insulin or blood glucose concentrations. In the obese patients, however, plasma GH concentrations remained low during the oral glucose tolerance test, and were not modified by bromocriptine. Blood glucose and plasma insulin concentrations were also unchanged. Plasma GH and plasma 11-hydroxycorticosteroid responses to insulin-induced hypoglycaemia were unaffected. Serum prolactin concentrations which were raised in five anorexic patients and marginally raised in two obese subjects, fell significantly in both groups during treatment. We observed no consistent weight changes in either groups.     

Influence of low doses of naloxone on pituitary secretion in man

Summary Naloxone 0.8 mg im administered to eight healthy subjects did not affect the serum levels of GH, LH, FSH, PRL, TSH and cortisol. Pretreatment with naloxone 0.8 mg increased TRH-induced TSH and PRL release in six healthy subjects. The same pretreatment caused an enhancement of haloperidol-induced PRL secretion in further other group of six subjects.     

Oral application of citalopram (20 mg) and its usefulness for neuroendocrine challenge tests

The present study was conducted to investigate whether a single oral dosage of 20 mg of the selective serotonin reuptake inhibitor citalopram could be used as a tool to stimulate hormone secretion in neuroendocrine challenge paradigms. A total number of 48 healthy male subjects received either 20 mg citalopram or placebo in a randomized, double-blind cross-over design at an interval of 1 wk between both sessions. Citalopram was well tolerated without side-effects. Growth hormone (GH), prolactin (Prl) and cortisol (Cort) were determined in blood samples obtained at different time-points across the experiment according to drug kinetics. While GH and Prl were not changed after citalopram Cort levels increased as compared to the placebo condition, significantly about 2 h after drug intake. Results will be discussed in respect of the question of whether or not Prl and GH responses after treatment with i.v. applications of SSRIs reflect sertonergic involvement.     

Amperozide – effect on prolactin release in the rat

Amperozide, a new putatively antipsychotic drug was investigated for its effect on prolactin release in the rat. A significant decrease in the plasma concentration of prolactin was found at 30 minutes after treatment with amperozide. However, there was no effect of amperozide on prolactin release from isolated pituitary cells. These results suggest that there is no direct effect of amperozide on the pituitary lactotrophs and that the attenuation of prolactin secretion in vivo is mediated at a higher level.     

The interaction of benzodiazepines with thyrotropin-releasing hormone receptors on clonal pituitary cells.

1. Seven benzodiazepines were investigated for their ability to interact with receptors for thyrotropin-releasing hormone (TRH) on GH3 and GH4C1 pituitary tumour cells. 2. Midazolam and chlordiazepoxide were the most potent inhibitors of TRH-induced [3H]-inositol phosphate formation with Ki values in the low micromolar range. The antagonism was competitive in nature and was increased in potency at sub-physiological temperatures. 3. None of the agents examined antagonized bombesin-induced [3H]-inositol phosphate formation in GH4C1 cells. 4. While the ability of benzodiazepines to interact with the GABA receptor-chloride channel ionophore is markedly stereospecific, little difference was evident in the ability of (+)- and (-)-4-methylmidazolam (Ro 21-5656 and Ro 21-5657) to compete with TRH at its receptor. 5. Recently it has been suggested that, in contrast to phosphatidylinositol hydrolysis, the TRH-induced breakdown of phosphatidylinositol polyphosphates is transient in clonal pituitary cells. Addition of chlordiazepoxide to TRH-stimulated GH3 cells up to 60 min after initiating the reaction leads, however, to an immediate decline in the cellular content of inositol trisphosphate. This indicates that TRH-induced phosphatidylinositol 4,5-bisphosphate hydrolysis is not transient.     

Effects of chronic sultopride treatment on endocrine systems in psychotic women

The effects of chronic sultopride treatment on endocrine systems were studied using five schizophrenic women. Sultopride, an antipsychotic drug, was administered orally three times daily for 5 weeks in a daily dose of 300–600 mg. The serum prolactin levels increased significantly after 1 day of treatment, reaching a maximum at 1 week and remaining elevated during treatment. The serum GH levels declined temporarily after 1 week of treatment and then returned to normal values after 3–5 weeks of treatment. Sultopride had no significant effects on LH, FSH, TSH, insulin, estradiol-17 and cortisol basal levels. Serum sultopride levels measured by radioimmunoassay remained steady during treatment. These results showed that sultopride stimulates prolactin secretion in schizophrenic women, probably by blocking pituitary dopamine receptors.     

Clinico-laboratory research on the pharmacodynamic characteristics of Rigevidon

A contraceptive effect of Rigevidon depends on the drug influence on cyclic secretion of gonadotropic hormones. Rigevidon fails to exert a significant effect on prolactin secretion. The drug withdrawal results in a comparatively rapid restoration (within the first three months) of the generative function.     

Effect of the anxiolytic drug buspirone on prolactin and corticosterone secretion in stressed and unstressed rats

Buspirone is an atypical anxiolytic drug that exerts its action at a receptor site other than the GABA-benzodiazepine-chloride ionophore complex. The present study examined the effect of buspirone on plasma prolactin and corticosterone levels in both control and stressed rats. In unstressed rats, buspirone produced dose-dependent increases in plasma prolactin and corticosterone levels. The minimal doses of buspirone which led to significant elevations in plasma prolactin and corticosterone levels were 1.0 and 2.0 mg/kg (IP), respectively. The effect of buspirone on both hormones was maximal 30 minutes after injection. The plasma levels of prolactin and corticosterone were significantly elevated in rats that were stressed using a conditioned fear paradigm. Buspirone produced a dose-dependent attenuation of the stress-induced increase in prolactin secretion. The stress-induced increase in corticosterone secretion was inhibited by the 0.5 mg/kg (IP) dose but not by the 2.0 mg/kg (IP) dose of buspirone, which increased corticosterone secretion both in stressed and unstressed rats. These data suggest that the effect of buspirone on plasma prolactin and corticosterone levels may be mediated by two different mechanisms of action.