Influence of serotonergic and adrenergic antagonists on TRH-induced prolactin release in the monkey.

The influence of methysergide, cyproheptadine and SQ 10,631 (serotonergic receptor blockers) at the dose of 35 μg/kg, 50 μg/kg and 5 mg/kg, respectively, and propranolol, phentolamine and phenoxybenzamine (adrenergic receptor blockers) at the dose of 1 mg/kg on TRH-induced prolactin release was studied in sexually mature female monkeys. The serotonergic antagonists had no effect on TRH-induced prolactin release. Both β and α adrenergic antagonist gave a similar potentiation of the TRH-induced prolactin response but only phenoxybenzamine plus TRH was statistically different (P < 0.05) from TRH alone. The effect of the adrenergic receptor blockers is believed to be due to actions on dopamine receptors.     

Influence of adrenergic antagonists and apomorphine on prolactin release induced by serotonergic antagonists in the monkey.

The influence of adrenergic receptor blockers on the prolactin releasing effect of methysergide and cyproheptadine was examined in sexually mature female monkeys under ketamine anesthesia. Propranolol, a β-adrenergic blocker, at a dose of 1 mg/kg did not alter the prolactin releasing action of 0.1 mg/kg of methysergide but significantly potentiated (P < 0.025) the prolactin releasing action of 0.5 mg/kg of cyproheptadine. Phentolamine and phenoxybenzamine, both α-adrenergic blockers, at 1 mg/kg blunted the prolactin releasing effect of methysergide and cyproheptadine, but the pattern of prolactin blockade was different between the two putative antiserotonergic drugs. The prior administration of apomorphine, 4 mg/kg, a dopamine receptor stimulator, blocked the prolactin releasing effect of methysergide and cyproheptadine. Evidence presented here and from the literature indicate that the prolactin releasing action of methysergide and cyproheptadine is mediated by an antidopaminergic action directly on the pituitary.     

Stimulation of prolactin secretion by morphine: role of the central serotonergic system.

Unanesthetized male rats with indwellinh right atrial cannulae were injected with morphine (MOR) i.v. which produced a dose-related increase in plasma prolactin levels (PRL). This effect was blocked partially by naloxone (NAL) at a dose of 0.06 mg/kg and totally by 0.6 mg/kg NAL. Interruption of central serotonergic neurotransmission by receptor blockade, with metergoline (MET) or cyproheptadine (Cypro), inhibition of tryptophan hydroxylase by para-chlorophenylalanine or destruction of serotonin neurons by 5, 7-dihydroxytryptamine antagonized the morphine (3 mg/kg) induced elevation in PRL release. Depression of dopaminergic activity with α-methyl-para-tyrosine elevated the basal PRL levels, but it did not prevent a further increase of prolactin levels by morphine (3 mg/kg). These data are compatible with the hypothesis that morphine stimulates PRL release by activation of the central serotonergic system.     

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.     

Involvement of some 5-HT receptors in methamphetamine-induced locomotor activity in mice.

Effects of some selective 5-HT antagonists on methamphetamine-induced locomotor activity were investigated in male mice in order to study whether this effect of methamphetamine is selectively or at least partially, induced through stimulation of a specific serotonin receptor subtype. Methamphetamine (1.5 mg/kg, IP) produced a significant increase in locomotor activity. Methamphetamine-induced hyperactivity by the above mentioned dose was significantly antagonized by NAN-190 ( 5-HT(1A) antagonist) at a dose of 4 mg/kg, IP, methiothepin (5-HT(1B/1D) antagonist) at a dose of 0.1mg/kg, IP or mianserin ( 5-HT(2C) antagonist) at a dose of 8 mg/kg, IP. On the other hand, methysergide ( 5-HT(2A/2B) antagonist) at a dose of 1mg/kg, IP or ondansetron ( 5-HT(3) antagonist) at a dose of 0.5mg/kg, IP potentiated the methamphetamine-induced hyperactivity. None of the above mentioned doses of 5-HT antagonists altered the spontaneous activity of mice when administered alone. The results of the present study indicate a possible role for serotonergic mechanisms, in addition to the catecholaminergic systems, in the locomotor stimulant activity of methamphetamine in mice. This role is possibly mediated through direct stimulation of some 5-HT receptor subtypes. Stimulation by methamphetamine of 5-HT(1A), 5-HT(1B/1D) and/or 5-HT(2C) receptor subtypes may result in hyperactivity, whereas stimulation by methamphetamine of 5-HT(2A/2B) and/or 5-HT(3) receptor subtypes may result in decreased activity.     

Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists.

Acute treatment with delta9-tetrahydrocannabinol [delta9-THC; 0.5 or 1.0 mg/kg b.w. intravenously (i.v.)], the major psychoactive constituent of marijuana, produces a dose-related suppression of pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To determine whether delta9-THC produces this response by altering neurotransmitter and/or neuropeptide systems involved in the regulation of LH secretion, ovariectomized rats were pretreated with antagonists for dopamine, norepinephrine, serotonin, or opioid receptors, and the effect of delta9-THC on LH release was determined. Pretreatment with the D2 receptor antagonists butaclamol (1.0 mg/kg b.w., intraperitoneally) or pimozide [0.63 mg/kg, subcutaneously (s.c.)], the opioid receptor antagonists naloxone (1-4 mg/kg, i.v.) or naltrexone (2 mg/kg, i.v.), the noradrenergic alpha2-receptor antagonist idazoxan (10 microg/kg, i.v.), or the serotonin 5-HT(1C/2) receptor antagonist ritanserin (1 or 5 mg/kg b.w., i.p.), did not alter delta9-THC-induced inhibition of pulsatile LH secretion. Pretreatment with a relatively high dose of the beta-adrenergic receptor blocker propranolol (6 mg/kg, i.v.) attenuated the ability of the low THC dose to inhibit LH release; however, lower doses of propranolol were without effect. Furthermore, the ability of a relatively nonspecific serotonin 5-HT(1A/1B) receptor antagonist pindolol (4 mg/kg, s.c.) or the specific 5-HT1A receptor antagonist WAY-100635 (1 mg/kg, s.c.) to significantly attenuate THC-induced LH suppression indicates that activation of serotonergic 5-HT1A receptors may be an important mode by which THC causes inhibition of LH release in the ovariectomized rat.     

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.     

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.     

Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers

Leptin regulates energy homeostasis and body weight by balancing energy intake and expenditure. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion, is capable of initiating intestinal nutrient absorption. Vagal afferent neurons also express receptors for both CCK and leptin, which are believed to interact in controlling food intake. The present study was undertaken to investigate the central and peripheral effects of leptin on gastric emptying rate. Under anesthesia, male Sprague-Dawley rats (250-300 g) were fitted with gastric Gregory cannulas (n=12) and some had additional cerebroventricular cannulas inserted into their right lateral ventricles. Following recovery, the rate of gastric emptying of saline (300 mOsm/kg H(2)O) was determined after instillation into the gastric fistula (3 ml, 37 degrees C, containing phenol red, 60 mg/l as a non-absorbable dilution marker). Gastric emptying rate was determined from the volume and phenol red concentrations recovered after 5 min. Leptin, injected intraperitoneally (i.p.; 10, 30, 60, 100 microg/kg) or intracerebroventricularly (i.c.v.; 5, 15 microg/rat) 15 min before the emptying, delayed gastric emptying rate of saline at the dose of 30 microg/kg or 15 microg/rat (p<0.001). When CCK(1) receptor blocker L-364,718 (1 mg/kg, i.p.), CCK(2) receptor blocker L-365,260 (1 mg/kg, ip) or adrenergic ganglion blocker bretylium tosylate (15 mg/kg, i.p.) was administered 15 min before ip leptin (30 microg/kg) injections, leptin-induced delay in gastric emptying was abolished only by the CCK(1) receptor blocker (p<0.001). However, the inhibitory effect of central leptin on gastric emptying was reversed by adrenergic blockade, but not by either CCK antagonists. Our results demonstrated that leptin delays gastric emptying. The peripheral effect of leptin on gastric motility appears to be mediated by CCK(1) receptors, suggesting the release of CCK and the involvement of vagal afferent fibers. On the other hand, the central effect of leptin on gastric emptying is likely to be mediated by adrenergic neurons. These results indicate the existence of a functional interaction between leptin and CCK receptors leading to inhibition of gastric emptying and short-term suppression of food intake, providing an additional feedback control in producing satiety.     

Effect of antiepileptic drugs on metrazol convulsions during ontogenesis in the rat

The effect of ethosuximide, dipropylacetate and clonazepam on metrazol convulsions induced by a dose of 80 mg/kg was studied in 314 male albino rats aged from 5 days to adult. In a standard dose of 125 mg/kg, ethosuximide reliably protected only adult and 25-day-old rats, i.e. the age groups in which a mature minimal seizure was the only type of convulsion induced; in younger animals, not even a much higher dose (tested in 12-day-old rats) afforded reliable protection. Dipropylacetate and clonazepam had a manifest protective effect in all age groups, irrespective of the type of seizure. Isolated myoclonic jerks were less sensitive to antiepileptics and only dipropylacetate blocked them in the youngest age groups. In 21-day-old and older animals dipropylacetate induced stereotype head movement reminiscent of the serotonergic stereotypy described in the literature.     

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.     

Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task

The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently.     

The effect of alpha- and beta-adrenergic antagonists of the self-stimulation phenomenon

In an attempt to evaluate the possible existence of alpha- and/or beta- adrenergic components of the self-stimulation reward system, rats were injected (i.p.) with chlorpromazine hydrochloride (2.5 mg/kg), phentolamine hydrochloride (5 mg/kg), and propranolol hydrochloride (10 mg/kg). The alpha- adrenergic antagonists (chlorpromazine and pehntolamine) inhibited self-stimulation but the beta-adrenergic blocker (propranolol) was without significant effect. Self-stimulation is apparently mediated by the alpha-adrenergic system.     

The effect of three novel thromboxane A2 receptor antagonists (S-1452, AA-2414 and ONO-3708) on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs.

The effects were studied of three novel thromboxane A2 (TXA2) receptor antagonists (S-1452, AA-2414 and ONO-3708) on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs. Three TXA2 antagonists at doses of between 1 and 10 mg/kg administered orally 1 h before the challenge clearly inhibited the pulmonary pressure increase. At a dose of 10 mg/kg, all three antagonists inhibited the pulmonary pressure increase caused by leukotriene D4 (LTD4) and U-46619, but not that caused by histamine. The decrease in peripheral platelet counts caused by Forssman anaphylaxis was also clearly inhibited by the three TXA2 antagonists. However, the decreased peripheral leukocyte counts were unaffected by the three agents. The decrease in serum complement activity (CH50) was inhibited by S-1452 and AA-2414 at a dose of 10 mg/kg. In bronchoalveolar lavage fluid (BALF), significant increases in eosinophils and neutrophils were observed after Forssman anaphylaxis. Three TXA2 antagonists at a dose of 10 mg/kg (except for AA-2414 on eosinophils) did not affect the changes of leukocyte counts in BALF. Moreover, increases in the TXB2 and 6-keto-PGF1 alpha levels of the BALF brought about by Forssman anaphylaxis were unaffected by the three TXA2 receptor antagonists. Histamine and LTD4 were not changed in the BALF after Forssman anaphylaxis. These results indicate the efficacy of TXA2 receptor antagonists on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs by direct antagonism to released TXA2.     

Enhanced prolactin inhibition following chronic treatment with haloperidol and morphine

Withdrawal from chronic haloperidol or morphine treatment resulted in lower circulating levels of serum prolactin in male rats. A low dose of apomorphine (0.32 mg/kg), which had no effect on serum prolactin in untreated rats, diminished serum prolactin in the treated rats. A lower dose of apomorphine (0.08 mg/kg) also ineffective in control rats, elevated serum prolactin in the treated rats.     

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

Intravenous injection of 600 μg 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-PGF_1α 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.     

Elevation of serum prolactin acutely after administration of p-chloroamphetamine in rats

p-Chloroamphetamine hydrochloride (0.5-10 mg/kg, i.p.) caused a rapid (within 30 minutes), dose-related increase in serum prolactin concentration in male rats. The effect was antagonized by pretreatment with p-chlorophenylalanine, an inhibitor of serotonin synethesis, or by metergoline, a serotonin receptor antagonist. The acute elevation of serum prolactin may have been mediated by the release of serotonin by p-chloroamphetamine.     

The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats

It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET(B) receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, indomethacin, with those of two selective COX-2 inhibitors, celecoxib and lumiracoxib, on ET-1-induced fever in rats. Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 mug/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli. Lower doses of celecoxib had partial (2.5 mg/kg) or no effect (1 mg/kg). Indomethacin (2 mg/kg ip) partially inhibited fever induced by LPS but had no effect on ET-1-induced fever. The levels of PGE(2) and PGF(2alpha) in the cerebrospinal fluid (CSF) of pentobarbital sodium-anesthetized rats were significantly increased 3 h after the injection of LPS or ET-1. The latter increase was abolished by celecoxib at all tested doses and by indomethacin. In conclusion, selective COX-2 inhibitors were able to prevent ET-1-induced fever, indicating a role for COX-2 in this phenomenon. However, the fact that reduced CSF PG levels obtained with indomethacin and a low dose of celecoxib are not accompanied by changes in fever induced by ET-1, along with the lack of inhibitory effects of indomethacin on ET-1 fever, suggests that the latter might also involve COX-2-independent mechanisms.     

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.     

Measurement of serum prolactin and the effect of ketamine anesthesia on serum prolactin levels in cynomolgus monkeys (Macaca fascicularis)

The effect of an anesthetic, ketamine, on the serum prolactin level was examined in wild-originating female cynomolgus monkeys (Macaca fascicularis) imported from South East Asia. Serum prolactin levels were measured by the homologous radioimmunoassay system which was developed for human prolactin. The validity was confirmed by using an extract of pituitary gland from a female cynomolgus monkey as well as serum and amniotic fluid from a pregnant monkey. Additionally, serum luteinizing hormone (LH) levels were determined by the radioreceptor assay system developed in our laboratory using Leydig cells collected from rat's testes as a receptor fraction. The experiment was repeated three times at one-month interval, using twenty animals that were divided into three groups consisting of 5, 7 and 8 monkeys each. In the first experiment, the first group was injected with physiological saline and the second and third groups were intramuscularly given ketamine at a dose level of 5 mg/kg B.W. and 15 mg/kg B.W., respectively. In the second experiment, the first and second groups were given ketamine at a dose of 5 mg/kg B.W. and of 15 mg/kg B.W., respectively, and the third group was served as control injected with saline. In the third experiment, the first and third groups were administered with 15 mg/kg and 5 mg/kg of ketamine and the second group was injected with saline. In short, all of the twenty monkeys received the three different treatments for two months. The serum prolactin level showed a marked increase after the administration of ketamine.(ABSTRACT TRUNCATED AT 250 WORDS)