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PubMed1988

Methysergide potentiates the hyperactivity produced by MDMA in rats.

Although some substituted amphetamines, like MDA, produce a combination of sympathomimetic stimulation and perceptual alterations, the psychoactive qualities of MDMA are less distinctive. MDMA binds to serotonergic receptors and has been shown to potently deplete brain serotonin concentrations. Biochemical and behavioral evidence suggests that MDMA may also act on the dopamine system. The present study explored the effects of blocking serotonin receptors on MDMA and amphetamine induced locomotor hyperactivity in rats. Locomotor activity was measured in photocell cages for 120 minutes following injection of methysergide (0, 2.5, 5, 10 mg/kg) or methysergide in combination with amphetamine (0.5 mg/kg) or MDMA (10 mg/kg). Methysergide, which had no effect on its own, significantly potentiated the locomotor hyperactivity produced by MDMA but not amphetamine. Thus, the intrinsic serotonergic agonist properties of MDMA may actually counteract the indirect sympathomimetic effects thought to be responsible for the locomotor hyperactivity MDMA produces.

3,4-Methylenedioxyamphetamine↗
PubMed1993

Effects of p-chlorophenylalanine and methysergide on the performance of a working memory task.

The present study investigated the effects of serotonergic dysfunction on working memory. Therefore, the effects of inhibition of serotonin [5-hydroxytryptamine (5-HT)] synthesis induced by p-chlorophenylalanine (p-CPA) and pharmacological blockade of 5-HT receptors by methysergide on the performance of rats in a delayed nonmatching to position task assessing spatial working memory were studied. Methysergide (1.0, 5.0, or 15.0 mg/kg) significantly disrupted behavioral activity of rats and decreased the percent correct total responses. However, the impairment in the percent correct responses was delay independent, indicating a nonmnemonic disruption of the performance. p-CPA (500 mg/kg/day x 3) induced an almost total depletion (> 97%) of frontal cortical and hippocampal serotonin and its major metabolite 5-hydroxyindoleacetic acid and slightly affected noradrenergic and dopaminergic systems. p-CPA treatment did not affect the percent correct responses. However, the behavioral activity of rats was slightly decreased by p-CPA. The disruptions in behavioral activity and the percent correct responses induced by methysergide (2.0 mg/kg) were not abolished by p-CPA. The present results do not support any important role for the serotonergic system in spatial working memory as assessed using the delayed nonmatching to position task.

Animals↗
PubMed1986

Effects of receptor blockers (methysergide, propranolol, phentolamine, yohimbine and prazosin) on desimipramine-induced pituitary hormone stimulation in humans--II. Prolactin.

In this report the effects of various receptor blockers on desimipramine (DMI)-induced prolactin (PRL) secretion in healthy male subjects are presented. Each trial consisted of two administrations: one of DMI i.v. alone and one of DMI i.v. in combination with the respective receptor blocker: methysergide (serotonin (5-HT) receptor blocker), propranolol (beta receptor blocker), phentolamine (alpha-1/alpha-2 receptor blocker), yohimbine (alpha-2 greater than alpha-1 receptor blocker), and prazosin (alpha-1 receptor blocker). Following administration of methysergide (12 mg p.o., n = 12), a significantly lower (p less than 0.01) DMI-induced PRL secretion compared to DMI alone in another group of subjects (n = 12) was observed. Combined administration with propranolol (15 mg i.v.) significantly enhanced the DMI-induced PRL secretion compared to DMI 50 mg i.v. alone (n = 18, incomplete block design) (p less than 0.01). Neither combined administration with phentolamine (60 mg i.v., n = 12), yohimbine (10 mg i.v., n = 6), nor prazosin (1 mg p.o., n = 12) significantly influenced the DMI-induced PRL secretion compared to DMI alone in the same subjects. The results of the present study, especially the inhibitory effect on DMI-induced PRL secretion of methysergide, indicate that the primarily noradrenaline (NA) and lesser serotonin (5-HT) reuptake inhibiting antidepressant DMI stimulates PRL secretion via 5-HT neurons. Furthermore, the significantly enhanced PRL release following combined administration of DMI and propranolol suggests that a noradrenergic inhibitory effect also may be involved in the transmission of the PRL stimulus.

Blood Glucose↗
PubMed1995

Effects of methysergide and ritanserin on the prolactin and thyrotropin responses to TRH in depressed patients.

Despite extensive study of the effects of various pharmacological agents on the thyrotropin (TSH) and prolactin (PRL) responses to TRH challenge, the effect of serotoninergic agents remains inconclusive. We studied the effect of the serotonin antagonists methysergide (non-selective 5-HT1/5-HT2 blocker with dopaminergic properties) and ritanserin (selective 5-HT2 blocker) on the TSH and PRL responses to TRH stimulation in two groups of medication-free female depressed patients in a double-blind, within-subject design. Methysergide was found to decrease significantly the PRL response to TRH, while ritanserin had no effect. Neither compound influenced the TSH response. Results suggest that 5-HT2 mechanisms do not mediate the PRL and TSH responses to TRH challenge in depression. The reduction in PRL observed after methysergide is probably due to either 5-HT1 or dopaminergic mechanisms.

Aged↗
PubMed1998

Intrathecal methysergide antagonizes the antinociception, but not the hyperalgesia produced by microinjection of baclofen in the ventromedial medulla of the rat.

Microinjection of baclofen, a gamma-aminobutyric acidB (GABA[B]) receptor agonist, in the nucleus raphe magnus (NRM) or nucleus reticularis gigantocellularis pars alpha (NGCpalpha) of the rat produces antinociception at doses of 0.1-1.0 ng and hyperalgesia at doses of 30-150 ng in the tail-flick test. The antinociception is proposed to result from disinhibition of spinally-projecting neurons in this region that contain serotonin. The hyperalgesia is proposed to result either from inhibition of these neurons or from disinhibition of a serotonergic pain facilitatory pathway that also originates in this area of the ventromedial medulla. To determine the involvement of bulbospinal serotonergic pathways in the biphasic effects of baclofen, rats were pretreated intrathecally with either 30 microg of methysergide or saline. Ten minutes later, either saline, 0.5 ng or 150 ng of baclofen was microinjected in the NRM and NGCpalpha, and alterations in nociceptive threshold were assessed by the tail-flick and hot-plate tests. Intrathecal pretreatment with methysergide prevented the increase in tail-flick latency produced by 0.5 ng of baclofen, but did not prevent the decrease in tail-flick latency produced by 150 ng of baclofen. Neither dose of baclofen altered hot-plate latency and this lack of effect was unchanged by methysergide. These data support the idea that the antinociceptive effect of low doses of baclofen in the tail-flick test is mediated by disinhibition of a bulbospinal serotonergic projection and release of serotonin in the spinal cord. These data also suggest that the hyperalgesia produced by high doses of baclofen does not result from disinhibition of a serotonergic pain facilitatory pathway, but rather from direct inhibition of tonically-active pain inhibitory neurons in the NRM and NGCpalpha.

Analgesics↗
PubMed1984

Simulation of acute myopericarditis by constrictive pericardial disease with endomyocardial fibrosis due to methysergide therapy.

Methysergide ( Sansert ) has been associated with numerous fibrotic disorders. In particular, multiple cardiac lesions have been described in cases where methysergide was thought to have played a causative role. A patient is described who presented with cardiac findings suggestive of acute myopericarditis . An inflammatory myocarditis was subsequently excluded by endomyocardial biopsy. Hemodynamic findings suggested the presence of constrictive pericarditis or restrictive cardiomyopathy, or both. Radiographic evidence of constrictive pericarditis and biopsy evidence of endocardial fibrosis were documented in this patient with a long history of interrupted methysergide therapy.

Acute Disease↗
PubMed1992

Effect of topical and intracameral methysergide on calcitonin gene-related peptide-induced irritative changes in the rabbit eye.

Calcitonin gene-related peptide (CGRP) is a neuropeptide localized in the ocular sensory nerves. It is responsible for most of the irritative changes in the rabbit eye in neurogenic inflammation, namely vasodilation in the anterior uvea, breakdown of the blood-aqueous barrier and increase in the intraocular pressure. In the present study, intracameral methysergide inhibited the CGRP-induced irritative changes in the rabbit eye. Provided that sufficient concentration of methysergide could be reached in the anterior chamber after topical application, it might be possible to use locally administered methysergide to limit different pathophysiological conditions in the eye in which CGRP is involved.

Administration, Topical↗
PubMed1979

Measurement of activity of 5-HT antagonists following oral administration in man: a comparison of methysergide and BW501.

1 Oral doses of BW501 and methysergide administered to healthy volunteers inhibited the ex vivo platelet aggregation response to 5-hydroxytryptamine (5-HT). 2 Two volunteers received 100 mg BW501 and two received 10 mg BW501 and aggregation response was measured immediately pre drug and at 1,3 and 24 h post drug. After 100 mg BW501 the response to 5-HT was completely inhibited at all times studied, after 10 BW501 a response too small to measure was apparent at 24 h only. 3 In two randomised crossover studies subjects received either 2 mg BW501 (nine subjects), 2 mg methysergide (six subjects) or no drug (nine subjects) and aggregation response to 5-HT was measured immediately pre drug and at 1, 2, 3, 5, 7, 24 h post drug. 4 Methysergide (2 mg) produced complete inhibition of aggregation for 24 h after dosing; following 2 mg BW501 the aggregation response was significantly lower than on the control occasion at 1 (P less than 0.01), 2 (P less than 0.01) and 3 (P less than 0.05) h post drug. The response was inhibited by rr%, 31% and 16% at these times respectively. 5 It is suggested that this technique provides a suitable method for demonstration of activity of 5-HT antagonists after oral dosing in man.

Administration, Oral↗
PubMedDate not supplied

Blockade by phentolamine of the potentiation of histamine-induced vasoconstriction caused by serotonin and methysergide in the rabbit ear artery.

1. In subconstrictor doses, both serotonin and methysergide potentiated the vasoconstrictor responses to histamine in the isolated artery of the rabbit ear. 2. In the presence of phentolamine (5 microgram/ml) the potentiating actions of serotonin and methysergide were significantly reduced. 3. This blocking action of phentolamine could be overcome by increasing the concentration of serotonin or by washing the preparation. 4. In arteries taken from rabbits pretreated with reserpine, serotonin still potentiated the response to histamine and phentolamine still blocked this potentiation. 5. The concentration of phentolamine required to block potentiation also blocked the direct constrictor response to serotonin. It did, however, produce a significantly greater blockade of the vasoconstrictor response to noradrenaline. 6. The results indicate that the action of phentolamine in blocking the vascular potentiation produced by serotonin and methysergide is not due to a blockade of alpha-receptors.

Animals↗
PubMed1998

Central methysergide prevents renal sympathoinhibition and bradycardia during hypotensive hemorrhage.

Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured in conscious rats during either hemorrhage or cardiopulmonary chemoreceptor stimulation with phenylbiguanide (PBG) after intracerebroventricular injection of the 5-HT1/5-HT2-receptor antagonist, methysergide (40 micrograms). Progressive hemorrhage caused an initial rise (109 +/- 33%) followed by a fall in RSNA (-60 +/- 7%) and a fall in HR (-126 +/- 7 beats/min). Methysergide delayed the hypotension and prevented both the sympathoinhibitory and bradycardic responses to hemorrhage. Systemic 5-HT3-receptor blockade did not influence responses to hemorrhage. The PBG infusion caused transient depressor (-25 +/- 6 mmHg), bradycardic (-176 +/- 40 beats/min), and renal sympathostimulatory (182 +/- 47% baseline) responses that were not affected by central methysergide (-20 +/- 6 mmHg, -162 +/- 18 beats/min, 227 +/- 46% baseline). These data indicate that a central serotonergic receptor-mediated component contributes to the sympathoinhibitory and bradycardic responses to hypotensive hemorrhage in conscious rats. Furthermore, the same central 5-HT-receptor populations involved in reflex responses to hypotensive hemorrhage probably do not mediate the sympathoinhibitory response to cardiopulmonary chemosensitive 5-HT3 receptors.

Animals↗
PubMed1978

Failure of nocturnal prolactin suppression by methysergide to entrain changes in testosterone in normal men.

In order to investigate further the postulated relationship between the secretion of PRL and testosterone, 10 normal young men were studied during polygraphically recorded sleep. Concentrations of LH and testosterone were measured in plasma every 20 min, and the results were analyzed in relation to sleep parameters and previously reported (J Clin Invest 56: 690, 1975) concentrations of PRL. All subjects were studied on a control night after placebo administration and on an experimental night after ingestion of the serotonin receptor blocker, methysergide. Analysis of variance revealed that concentrations of testosterone rose gradually during sleep on both nights, as has been noted in previous studies. Highest LH values occurred during stage 1 sleep, but were only 25% higher than the lowest values, which were seen in stage 4. As shown previously, PRL concentrations were markedly suppressed by methysergide treatment. However, no significant change in testosterone values were observed on the methysergide nights as compared to the control nights. When the data were analyzed by a correlational approach, again, no significant relation between concentrations of PRL and testosterone was found. Although these data do not support the concept that PRL-stimulated testosterone secretion occurs during the night in normal men, this study does not rule out the possibility that such a mechanism may be operative during daytime hours, or under conditions of PRL stimulation rather than PRL suppression.

Humans↗
PubMed2006

Methysergide-induced valvular heart disease: a report of 2 cases.

Methysergide is a serotonin antagonist and is used as a long-term prophylactic treatment for migraine. Although many patients experience adequate control of migraine episodes, methysergide has been reported to cause retroperitoneal and pleuropulmonary fibrosis. Cardiovascular side effects mainly in the form of valvular fibrosis have been less recognized. We report 2 cases of methysergide-related mitral valve fibrosis.

Female↗
PubMed1984

Effect of methysergide pretreatment on thrombin-induced pulmonary oedema in the rat.

Microembolic pulmonary oedema was induced by injection of thrombin (500 NIH units/kg body weight) i.v. in rats in which fibrinolysis had been inhibited by pretreatment with trans-4-aminomethyl-cyclohexanoid-carboxylic acid (AMCA). To evaluate the role of serotonin in this condition the effect of pretreatment with the antiserotonin compound methysergide (2.5 mg/kg body weight) on the amount of pulmonary oedema was studied. Pretreatment with methysergide resulted in a 20% decrease in lung weight in thrombin-treated rats. It caused a significant reduction of dilated lymph vessels, and of interstitial and alveolar oedema, as evaluated morphometrically. Methysergide pretreatment did not significantly alter the number of degranulated mast cells. Antiserotonin is thought to exert its effect by lowering the filtration pressure in the pulmonary microcirculation.

Animals↗
PubMedDate not supplied

[Effect of methysergide on behavior of rats with various levels of corticosteroids].

The effects of methysergide (metisergid), a nonspecific antagonist of type I and II serotonin receptors, on the character of the conditional reflex, learning and behavior of male rats was studied under conditions of low versus high content of corticosteroids. It was established that methysergide improved the ability of animals to acquire and reproduce the active avoidance reflex in the test animals with a deficit of the corticosteroid hormones, while no such effects were observed in rats with increased level of these hormones. Under conditions of the corticosteroid hormone deficit, methysergide stimulated the total locomotor activity in the open field test; in the excess of corticosteroids, the drug inhibited the emotional and grooming behavior components.

Adrenal Cortex Hormones↗
PubMed1976

Effects of methysergide in cats deprived of paradoxical sleep.

Methysergide maleate, a 5-hydroxytryptamine receptor blocker, was administered to cats deprived of paradoxical sleep for 48 hours. During the first six hours after methysergide, the latency to the first slow-wave sleep and paradoxical sleep episodes was increased and total sleep time decreased. The decrease in sleep reflects a loss of paradoxical sleep, while the amount of slow-wave sleep remained unchanged. Slow-wave sleep time, though unchanged in amount, was displaced to the end of the six-hour recording period. These results suggest that paradoxical sleep in cats is more sensitive to methysergide action than is slow-wave sleep.

Animals↗
PubMedDate not supplied

Prenatal alcohol exposure and offspring hyperactivity: effects of para-chlorophenylalanine and methysergide.

Pregnant Wistar rats were exposed to either a liquid diet containing ethanol, pair-fed an identical diet with sucrose substituted for ethanol, or received ad lib chow and water, during days 6-19 of gestation. Pups were injected with a dose of 100 mg/kg of para-chlorophenylalanine, 48 hr, 24 hr or immediately prior to activity testing at 16, 22 or 28 days of age. Further groups were injected with isotonic saline just prior to activity testing. Pups exposed to alcohol prenatally were more active than controls at 16 days of age. parachlorophenylalanine brought about significant increases in activity when injected 24 or 48 hr prior to testing in 16-day-old pups, and significant increases in activity when injected 24 hr prior to testing in 22- and 28-day-old pups. However, these effects of parachlorophenylalanine were similar regardless of prenatal treatment. In a second study, 16-day-old pups received saline, 0.5, 1.0 or 2.0 mg/kg of methysergide immediately prior to an activity test. Methysergide brought about a dose-related decrease in activity in all three groups of pups. Most importantly, the effects on activity of the methysergide were similar regardless of the treatment received during gestation. These data indicate that the hyperactivity associated with fetal alcohol exposure is unlikely to result from alterations in the ontogeny of a serotonergic system involved in response inhibition.

Age Factors↗
PubMed1980

5-Hydroxytryptamine receptors. Contractile activity and mode of inhibition by methysergide in mammalian intracranial and extracranial vessels.

The contractile effect of 5-HT on intra- and extracranial arteries from rabbit, cat, dog and man and its interaction with methysergide was investigated. ED50 and EAm values for 5-HT from both types of arteries differed. Intracranial arteries stimulated by 5-HT were more sensitive to methysergide than extracranial arteries. In intracranial vessels the methysergide antagonism is non-competitive while in extracranial it is competitive. These differences might suggest a heterogeneity of 5-HT receptors located within the cranial circulation.

Animals↗
PubMed1994

Effect of indomethacin, renzapride, methysergide, ketanserin, granisetron and citalopram on serotonin-induced fluid accumulation in pig jejunum.

The purpose of this study was to elucidate the intestinal serotonin (5-HT) receptor subtypes involved in fluid transport in the pig jejunum in vivo. The fluid accumulating effect of intraluminally administered 5-HT, renzapride, methysergide, ketanserin, granisetron, citalopram and intravenous indomethacin, was tested in tied-off loops in vivo. 5-HT caused a dose-dependent fluid accumulation, which was reduced by indomethacin by about 30%. Renzapride, methysergide, ketanserin, granisetron and citalopram all caused fluid accumulation. Taking into account these fluid accumulating effects, renzapride, methysergide, ketanserin and granisetron reduced the fluid accumulating effect of 5-HT, giving a maximal reduction of 70, 46, 76, and 80%, respectively. These data suggest the existence of intestinal 5-HT receptor subtypes involved in fluid transport in the pig jejunum. The antagonistic effects of indomethacin, ketanserin and granisetron, suggest the involvement of prostaglandins, as well as the 5-HT2 and the 5-HT3 receptor subtypes in the fluid accumulating response of 5-HT.

Animals↗