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PubMed1982

Effects of 5-HT receptor agonists and antagonists on a reflex response to radiant heat in normal and spinally transected rats.

Tail-flick latency (TFL) was tested in intact and spinally transected rats. Spinal transection permanently lowered the TFL by 25-30%. A diurnal rhythm in nociception was found in intact but not in spinal rats with maximum sensitivity during the early light period. Administration of the 5-hydroxytryptamine (5-HT) receptor antagonists metergoline (0.06-2.0 mg/kg), mianserin (1.0 and 5.0 mg/kg) or methiothepin (0.1-2.5 mg/kg) reduced the TFL of normal rats to the same level as that of the transected animals. The diurnal variation in TFL was also abolished by metergoline. Neither drug changed the TFL of the transected rats. The 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 0.5-2.0 mg/kg) induced the 5-HT syndrome in intact rats and elicited spinal reflexes in the transected animals. Concomitantly, the TFLs of both groups were elevated to the same maximum level, approximately 25% above normal TFL of intact rats. Transected rats consistently responded to lower doses than intact rats, indicating 5-HT receptor supersensitivity. The 5-MeODMT effects were reversed by administration of 5-HT antagonists. Administration of the 5-HT precursor dl-5-hydroxytryptophan (200 mg/kg), after inhibition of peripheral decarboxylation by carbidopa (75 mg/kg), also elevated the TFL and induced other behavioral signs of 5-HT stimulation. It is concluded tht there exists a tonic inhibitory influence with diurnal variations on spinal nociceptive reflexes in the rat. The data reported suggest that this inhibition is mediated by descending 5-HT pathways.

5-Hydroxytryptophan↗
PubMed1987

Water intake induced in rats by serotonin and 5-hydroxytryptophan: different mechanisms?

The present studies were designed to investigate further the mechanism by which water intake is induced in rats by peripheral administration of either serotonin (5HT) or its precursor 5-hydroxytryptophan (5HTP). Consistent with previous studies that have implicated mediation by the renal renin-angiotensin system (RAS), we now report that bilateral nephrectomy completely abolishes the drinking response to various doses of 5HT. In contrast, nephrectomy had little effect on the drinking induced by 5HTP. Thus, 5HTP may induce drinking by mechanisms other than its peripheral conversion to 5HT and subsequent activation of the RAS. The drinking responses to both 5HT and 5HTP were blocked by peripheral administration of the 5HT receptor antagonist, metergoline, but the drug was at least ten-fold more potent against 5HTP than 5HT. Intracerebroventricular (ICV) administration of metergoline also prevented the drinking response to peripherally-administered 5HTP. The drinking responses to both 5HT and 5HTP were enhanced by peripheral administration of low doses of an angiotensin I converting enzyme inhibitor, captopril. Collectively, these findings support previous conclusions that 5HT-induced intake of water is mediated exclusively by the renal RAS. However, 5HTP-induced drinking may additionally involve a renin-independent, serotonin-mediated mechanism, possibly in the brain.

5-Hydroxytryptophan↗
PubMed2005

Serotonin-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue culture.

The effects of serotonin (5-hydroxytryptamine; 5-HT) on vasopressin (VP) and oxytocin (OT) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP and OT contents of the supernatant were determined by radioimmunoassay after a 1 or 2 h incubation. Significantly increased levels of VP and OT production were detected in the tissue culture media following 5-HT administration, depending on the 5-HT dose. The elevation of NH hormone secretion could be partially blocked by previous administration of the 5-HT antagonist ketanserin or metergoline. WAY-100635 did not influence the increased VP secretion induced by 5-HT, but the elevated OT production was prevented by WAY-100635 before 5-HT administration. The application of WAY-100635, ketanserin or metergoline, after 5-HT administration proved ineffective. The results indicate that NH hormone release is influenced directly by the serotonergic system. The serotonergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary.

Animals↗
PubMed1998

Behavioral inhibition of light-induced circadian phase resetting is phase and serotonin dependent.

Circadian rhythms in Syrian hamsters can be phase shifted by light exposure during the subjective night and by a bout of wheel running induced during the subjective day. Interactions between photic and behavioral stimuli were examined by comparing phase shifts to 15 min, 50 lux light pulses with and without a bout of running induced by confinement to a novel wheel 30 min prior to and extending through light exposure. Light pulses 6 h after dark onset on the first night of constant dark induced phase advance shifts averaging 80 min. Wheel running attenuated these shifts by 45% on average (p<0.01). Light pulses 1 h or 2.25 h after dark onset induced phase delay shifts averaging 50 min and 20 min, respectively, that were not affected by stimulated running. A significant running response to the novel wheel was evident at all 3 time points, but was greater to wheel confinement at both times early in the night. Stimulated running alone early or late in the night did not produce significant phase shifts. Behavioral attenuation of phase advances to light late in the night was prevented by pretreatment with the general 5HT1 antagonist metergoline (2 mg/kg i.p.). Metergoline did not significantly attenuate running in novel wheels. These results indicate that modulation of light-induced phase shifts by behavior is phase dependent and may involve direct or indirect actions of serotonin within the circadian system.

Animals↗
PubMed1978

Inhibition of prolactin release by serotonin antagonists in hyperprolactinemic subjects.

Metergoline (4 mg) and methysergide (3 mg), two serotonin antagonists known to inhibit prolactin secretion in normal subjects, and the dopaminergic agonist, bromocriptine (2.5 mg) were orally administered in hyperprolactinemic patients. Mean serum prolactin concentration was significantly decreased between 120 and 240 min following the ingestion of all three drugs in comparison with a placebo; a consistent reduction to below 50% of basal values occurred in 10 of 14 patients after metergoline, in 5 of 10 after methysergide, and in 11 of 14 after bromocriptine administration. These data indicate that serotonin antagonists may acutely lower serum prolactin levels in hyperprolactinemic patients similarly to bromocriptine, though their mechanism of action is most likely different.

Adult↗
PubMed1998

An investigation into the effects of 5-HT agonists and receptor antagonists on ethanol self-administration in the rat.

Pharmacological manipulation leading to altered 5-HT function has been widely demonstrated to reduce ethanol intake in free choice tests. The aim of the present study was to examine the effects of a range of compounds known to influence 5-HT neurotransmission, including selective 5-HT receptor agonists and antagonists, on ethanol ingestion and maintained behaviour in an operant self-administration paradigm. Female Sprague-Dawley rats were trained to respond for 8% ethanol (v/v) in a 60-min test by a previously described technique. The number of responses and ethanol reinforcers (dipper deliveries), ethanol consumption (g/kg of body weight), and locomotor activity (LMA) were measured following administration of 5-HT agonists (5-HT, d-fenfluramine, fluoxetine, buspirone, TFMPP, and DOI) and antagonists (metergoline, ritanserin, and ondansetron) 30 min prior to testing. d-Fenfluramine, fluoxetine, buspirone, TFMPP, and DOI all produced a reduction in ethanol ingestion and maintained behaviour at doses that failed to reduce LMA. Conversely, metergoline and ritanserin only reduced ethanol self-administration at doses that concomitantly reduced LMA. 5-HT and ondansetron were without effect on any measure. These results demonstrate that, under the present experimental conditions, activation of central 5-HT1A, 5-HT1B, and 5-HT2 receptors reduced ethanol intake and reinforced behaviour in an operant paradigm.

Animals↗
PubMed1986

Evidence for serotoninergic system involvement in opioid control of luteinizing hormone secretion in man.

Endogenous opioid peptides tonically inhibit LH by acting on hypothalamic mechanisms which regulate LHRH secretion. Opiates increase hypothalamic serotonin turnover but the involvement of the serotoninergic system in the opioid mechanisms regulating LH secretion in man is not clear at present. This study was designed to evaluate whether the tonic inhibitory effect on LH secretion induced by opiates involves the serotoninergic system. We have studied 10 healthy young men (aged 20-28 years). Five subjects were infused with naloxone (10 mg/h for 3 h) before and 120 min after fenfluramine administration (60 mg orally) on two different occasions. In five other subjects naloxone was infused before and after metergoline pretreatment (8 mg on first and second day and 4 mg on the third day, orally, at 0 time of naloxone infusion). After fenfluramine, naloxone infusion failed to induce any increase in LH plasma levels; metergoline pretreatment significantly enhanced the naloxone-induced LH increase. These data suggest that in man a hypothalamic serotoninergic system may be involved in the opioid mechanisms regulating LH secretion.

Adult↗
PubMed1989

Muscarinic cholinergic, but not serotoninergic mediation of arginine vasopressin response to metoclopramide in man.

The possibility that metoclopramide (MCP) stimulates arginine vasopressin (AVP) secretion in man through a serotoninergic and/or a cholinergic muscarinic pathway was studied. Twenty normal male subjects were tested with MCP (10 mg in an i.v. bolus) alone or in the presence of the 5HT1 serotoninergic antagonist metergoline (10 mg/day p.o. in five divided doses for 4 days), the 5HT2 receptor blocker ketanserin (10 mg i.v. 5 min before MCP) (n = 10), the M1 and M2 muscarinic antagonist atropine (1.2 mg i.v. just before MCP administration) or the M1 muscarinic receptor blocker pirenzepine (40 mg i.v. 10 min before MCP) (n = 10). AVP doubled in response to MCP. the MCP-induced AVP rise did not change after metergoline, ketanserin or pirenzepine administration, whereas it was abolished by atropine. Additional experiments were performed in order to evaluate the effect of 1.2 mg atropine, given alone, on circulating AVP levels and whether the effect of atropine on the AVP response to MCP depends on the amount of the muscarinic antagonist (dose-response study). For these purposes, atropine was given alone to the same subjects previously tested with MCP plus atropine; furthermore, eight additional male subjects were tested with MCP plus atropine given in doses ranging from 0.8 to 1.4 mg. The results of these additional studies failed to show an effect of atropine alone on AVP secretion and demonstrated a dose-related inhibition of MCP-induced AVP rise by increasing atropine administration from 0.8 mg to 1.2 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Evidence for depressant 5-HT1-like receptors on rat brainstem neurones.

1. The technique of microiontophoresis was used to evaluate the contribution of 5-HT1-like, 5-HT2- and 5-HT3-receptors to the depressant effects of 5-hydroxytryptamine (5-HT) on neurones in the midline of the medullary brainstem of the rat in vivo. 2. Depressant responses to 5-HT were resistant to antagonism by the 5-HT2-receptor antagonist ketanserin and the 5-HT3-receptor antagonist MDL 72222 applied either microiontophoretically or administered systemically. 3. Microiontophoretic or systemic administration of the 5-HT antagonist metergoline, which shows nanomolar affinity for the 5-HT1-binding site, also failed to attenuate the depressant responses to 5-HT. 4. Systemic administration of high doses of methysergide (30-40 mg kg-1) attenuated the depressant responses to 5-HT but did not block depressant responses to GABA or excitatory responses to glutamate. 5. The depressant effects of 5-HT were potently mimicked by the 5-HT1-like receptor agonists 5-carboxamidotryptamine and 8-OH-DPAT. 6. These results indicate that neither 5-HT2-receptors nor 5-HT3-receptors are involved in the depressant effects of 5-HT on midline brainstem neurones. The depressant effects of 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and blockade of the response to 5-HT by high doses of methysergide suggests the involvement of 5-HT1-like receptors. The lack of effect of metergoline, however, indicates that this receptor may be different from any of the 5-HT1 binding sites yet described.

Animals↗
PubMed1988

Further studies of serotonergic activity in the regulation of the cold stimulated thyrotropin secretion in male rats.

Serotonergic agonists and antagonists were used to study the role of 5-HT in the regulation of thyrotropin (TSH) secretion in male rats. When given peripherally, the agonists like 5-HT, quipazine and m-chlorophenylpiperazine (mCPP) decreased dose-dependently the cold-stimulated TSH-secretion. The action of 5-HT was antagonized by metergoline but not by ketanserin. The effect of quipazine was counteracted by both antagonists. Small intraperitoneal doses of ketanserin seemed to be stimulatory on the TSH secretion while high doses of both ketanserin and metergoline clearly decreased the cold-stimulated TSH levels. Infusion of quipazine into the 3rd ventricle inhibited significantly the TSH cold-response whereas 5-HT and mCPP did not. The action of quipazine was only partially antagonized by ketanserin pretreatment. 5,7-dihydroxytryptamine (5,7-DHT) was used to make serotonergic lesions into different regions of the brain. The TSH lowering effects of intraperitoneal quipazine and mCPP were potentiated in the rats lesioned in the 3rd ventricle or bilaterally into the posterior hypothalamus but not in the rats lesioned bilaterally into the anterior hypothalamus. Hence serotonergic activity in the vicinity of the posterior part of the 3rd ventricle seems to decrease the cold-stimulated TSH secretion. Both 5-HT1 and 5-HT2 receptors appear to participate in this regulation.

Animals↗
PubMed1981

Immobility test: effects of 5-hydroxytryptaminergic drugs and role of catecholamines in the activity of some antidepressants.

Fenfluramine and m-chlorophenylpiperazine, two drugs purported to enhance central 5-hydroxytryptaminergic transmission, and metergoline, a 5-HT antagonist, did not modify the duration of immobility induced in rats made to swim in a restricted space. Nomifensine, desipramine and amineptine, three antidepressants known to block neuronal catecholamine uptake, significantly reduced the duration of immobility. Penfluridol, a dopamine antagonist at central receptors, counteracted the effect of nomifensine and amineptine but not that of desipramine. Propranolol and phenoxybenzamine respectively reduced the effects of desipramine and nomifensine but did not modify amineptine's effect. Metergoline pretreatment did not counteract the effect of any drug. The results indicate that various antidepressants can reduce the duration of immobility in rats by activating dopaminergic and/or noradrenergic mechanisms in the brain. Either alpha- or beta-noradrenergic receptors could contribute to the anti-immobility effects, depending on the drug used. The immobility test appears to be insensitive to drugs activating or reducing 5-HT-ergic mechanisms in the brain.

Animals↗
PubMed1977

Inhibition of cerebral cortical neurones by a 5-hydroxytryptaminergic pathway from median raphé nucleus.

Recent observations made in our laboratory have shown that metergoline is a selective 5-hydroxytryptamine (5-HT) antagonist in the cerebral cortex. Fluoxetine is a reportedly selective 5-HT neuronal uptake blocker. In the present investigation these drugs have been used to examine the existence of a putative 5-HT input to the cerebral cortex. In rats anaesthetized with a mixture of methoxyflurane, nitrous oxide, and oxygen, stimulation of the median raphé nucleus or of the ipsilateral cortical surface and iontophoretically applied 5-HT decreased the firing of the deep cerebral cortical neurones. Metergoline antagonized the 5-HT-induced depression and reduced the duration of inhibition produced by raphé nucleus stimulation. These results suggest that the cerebral cortical neurones are inhibited by an ascending 5-HT-containing pathway.

Animals↗
PubMed1980

Pharmacological evidence that stimulation of central serotonergic pathways increases renin secretion.

To determine if serotonin plays a role in the regulation of renin secretion, pentobarbital-anesthetized dogs were injected intravenously with drugs which modify serotonin metabolism. Renal perfusion pressure was kept constant by a clamp on the aorta proximal to the renal arteries. 5-Hydroxytryptophan (5-HTP) caused a significant increase (p less than 0.05) in arterial plasma renin activity (pra) that was abolished when peripheral and central aromatic amino acid decarboxylase activities were inhibited by administration of benserazide, but not reduced when only the peripheral decarboxylase activities were inhibited by administration of carbidopa. The serotonin receptor blocking drug metergoline also abolished the renin response to 5-HTP. L-Tryptophan in two different doses increased PRA. This increase was not reduced by carbidopa but was reduced or abolished by benserazide, metergoline, and renal denervation. The increase in PRA produced by 5-HTP and L-Tryptophan occurred without any change in blood pressure. 5-HTP had no effect on heart rate but L-Tryptophan reduced heart rate. These data indicate that 5-HTP and L-Tryptophan act on the central nervous system to produce an increase in renin secretion that is mediated via the renal nerves and occurs without a concomitant increase in sympathetic output to the heart or blood vessels. The increase appears to be due to the release of serotonin within the central nervous system.

5-Hydroxytryptophan↗
PubMed1980

Regulation of prolactin and growth hormone secretion. Site and mechanism of action of thyrotropin-releasing hormone, L-dopa and L-5-hydroxytryptophan in unanesthetized dogs.

A heterologous radioimmunoassay for canine prolactin was developed and used to study the role of catecholamines and indoleamines in the regulation of prolactin secretion in dogs. Females dogs were found to have a higher plasma prolactin concentration than male dogs. Thyrotropin-releasing hormone (TRH) increased plasma prolactin in male and female trained conscious dogs. L-Dopa blocked the increase produced by TRH, but this effect could be reversed by pretreatment with carbidopa, an inhibitor of the conversion of L-dopa to catecholamines outside the blood-brain barrier. The intravenous administration of the immediate precursor of serotonin, L-5-hydroxytryptophan (5HTP), caused an increase in plasma prolactin and growth hormone. The administration of the serotonin receptor blocker, metergoline, 18 and 3 h before 5HTP, significantly augmented the growth hormone response to 5HTP. In contrast, metergoline diminished the prolactin response to 5HTP. Pretreatment with carbidopa did not change the prolactin or growth hormone responses to 5HTP. These observations indicate that the dog is similar to other mammals in that females have greater plasma prolactin concentrations than males and TRH increases plasma prolactin. L-Dopa appears to act at a site outside the blood-brain barrier to prevent the prolactin response to TRH. The data suggest that 5HTP increases plasma prolactin via a serotonergic mechanism, whereas it increases plasma growth hormone via a different, nonserotonergic mechanism.

5-Hydroxytryptophan↗
PubMed1981

Effect of electrical stimulation of the dorsomedial hypothalamic nucleus on pulsatile LH release in ovariectomized rats.

The present experiments were carried out to examine the influence of electrical stimulation of the dorsomedial hypothalamic nucleus (DMH) on pulsatile LH release in ovariectomized rats, and the possible involvement of serotonin (5HT) in mediating any observed effects. Unanesthetized animals were bled continuously through jugular vein cannulae for an initial 1 1/2 h control period. Rats were then stimulated for two 1-hour periods, separated by a 45-min nonstimulation period. DMH stimulation suppressed pulsatile LH release and decreased mean blood LH levels during both stimulation periods in control rats as well as animals in which 5HT synthesis was inhibited by p-chlorophenylalanine or 5HT receptors were blocked by metergoline. The decrease in mean blood LH levels in all groups was due solely to an increase in the LH interpulse interval. LH pulses that did occur during the stimulation-induced suppression did not show a decreased LH pulse amplitude. Rather, in control and metergoline-treated animals this parameter increased during stimulation, suggesting a buildup of readily releasable LHRH and/or pituitary LH. Lastly, estradiol benzoate suppressed pulsatile LH secretion but did not reverse the inhibitory LH response to DMH stimulation. These experiments indicate that the DMH, because of neurons originating within this nucleus and/or fibers passing through, may be a brain region that influences pulsatile LH release in a suppressive manner. This effect is exerted solely on the periodicity of the process and not through a 5HT-mediated mechanism.

Animals↗
PubMed1980

Hyperprolactinemic primary amenorrhea: case report with successful prolactin-lowering treatment and review of the literature.

A 19-year-old girl with primary amenorrhea, galactorrhea, and hyperprolactinemia is described. Her high serum prolactin levels (95 ng/ml) did not increase after thyrotropin-releasing hormone and sulpiride, but markedly decreased after acute bromocriptine and metergoline administration. The results of other pituitary function tests were normal. Tomography of the sella turcica and CT scan of the skull were also normal. The patient was treated with metergoline, a prolactin-lowering drug which is believed to act as a serotonin antagonist, for 30 months. Serum prolactin rapidly decreased after institution of treatment, with actual normalization (less than 20 ng/ml) by the 3rd month. At this time the low serum luteinizing hormone levels began to rise and fluctuate in the normal follicular range. Galactorrhea disappeared, and menarche occurred during the 15th month of treatment. 15 further menstrual bleedings ensued over the following 15 months, albeit at irregular time intervals; ovulation was suggested by finding elevated serum progesterone levels in the presumed luteal phase by about 1 year following the menarche. The available data on 38 patients with primary amenorrhea and hyperprolactinemia reported in the literature are reviewed. 15 of them were treated with bromocriptine, and either pregnancy or cyclic menses occurred in 11. Hyperprolactinemic primary amenorrhea may be more common than previously recognized, and it may probably be successfully treated by prolactin-lowering drugs or by surgical ablation of a pituitary adenoma in a high percentage of cases.

Adult↗
PubMed1978

Serotonin receptor antagonists block a natural, short term surge in serum growth hormone levels.

Serum GH levels in untreated rats were found to increase spontaneously to over 300 ng/ml around the onset of darkness (1900 h) and then decrease to under 100 ng/ml by 2000 h. Pretreatment with the serotonin receptor blockers, metergoline (0.2, 0.5, 1, or 2 mg/kg) or cyproheptadine (1, 2, or 5 mg/kg), at 1800 h significantly blunted this physiological rise in serum GH. In rats bearing chronic right atrial cannulae from which blood samples were drawn every 15 min for 5 h, the administration of metergoline (1 mg/kg) was also observed to reduce plasma GH levels over a 3.25-h period. Serotonin-containing neurons in the brain thus seem to be involved in the physiological secretion of GH.

Animals↗
PubMed1988

Serotonergic mediation of a negative feedback effect of estrogen on luteinizing hormone release in ovariectomized rats.

Effects of the serotonin receptor antagonists ketanserin, metergoline, and methysergide on LH release were tested in ovariectomized (OVX) rats pretreated with estradiol benzoate (EB) (5 micrograms/100 g BW) on each of the 2 days preceding the experiment. LH concentration measured by RIA in plasma samples obtained at 10 min intervals was analyzed using the PULSAR computer program to identify and characterize pulses observed in the LH profile of each rat individually. Multiple pulses were identified in seven of seven OVX rats but in only two of eight OVX rats primed with EB. Multiple pulses were identified in OVX EB-primed rats pretreated with ketanserin (six of seven), metergoline (three of seven), and methysergide (six of eight). Administration of the serotonin (5HT) agonist quipazine (2 mg/kg iv) to OVX rats inhibited pulsatile LH release and depressed mean plasma concentrations for approximately 45 min. This inhibitory response was antagonized by pretreatment of the OVX animals with ketanserin. These results suggest that 1) quipazine inhibits pulsatile LH release in OVX rats by a serotonin2 receptor mechanism; and 2) the inhibitory effect of estrogen on pulsatile LH release may also be mediated, at least in part, via 5HT2 systems.

Animals↗