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At least 19 recordsLinked to original sources
PubMed1979

In vitro and in vivo disposition of 3H-methiothepin in brain tissues. Relationship to the effects of acute treatment with methiothepin on central serotoninergic receptors.

A single treatment with a large dose of methiothepin (20 mg/kg, i.p.) induced, as early as the 2nd day after injection, a significant increase (+20--35%) in the number of specific binding sites for 3H-5-HT in forebrain areas, particularly the hippocampus. Experiments with 3H-methiothepin indicated that the drug remained firmly bound to brain membranes thus maintaining a local concentration high enough to effectively block 5-HT receptors for 10--12 h after its peripheral administration. Accordingly, it can be concluded that the occupancy of central 5-HT receptor sites by methiothepin for several hours was sufficient to induce a supersensitivity phenomenon within the two following days. Although 3H-methiothepin was a useful marker for analyzing the disposition and the kinetics of the 5-HT antagonist in brain tissues, it could not be used as a specific ligand of 5-HT receptors in brain since under in vitro as well as in vivo conditions most of 3H-methiothepin bound to non-specific sites, especially to the lipid component of the membranes.

Adenylyl Cyclases↗
PubMed1986

Stereoselective blockade at the 5-HT autoreceptor and inhibition of radioligand binding to central 5-HT recognition sites by the optical isomers of methiothepin.

The enantiomers of the 5-HT autoreceptor antagonist methiothepin have been prepared and their activity as antagonists of the 5-HT autoreceptor and at the 5-HT recognition sites present in the frontal cortex of the rat have been evaluated. At the 5-HT autoreceptor, the order of potency as antagonists of 5-HT was (+)methiothepin (apparent pA2 5.95) less than (+/-)methiothepin (apparent pA2 6.62) less than or equal to (-)methiothepin (apparent pA2 6.81). At the 5-HT2 recognition site, the isomeric forms of methiothepin were potent (pIC50 approximately 8.2) and equiactive. At the subtypes of the 5-HT1 recognition sites, similar concentrations to those blocking the autoreceptor were effective and (+)methiothepin was less active than (-)methiothepin. It is concluded that the chiral association of methiothepin with the 5-HT autoreceptor provides further evidence for a pharmacological similarity between this receptor and the 5-HT1B subtype of the 5-HT1 recognition site.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Reduced head-twitch response to quipazine of rats previously treated with methiothepin: possible involvement of dopaminergic system.

Methiothepin has been reported to induce an increase of specific binding sites for 3H-5TH 2-3 days following a single administration of a large dose. The present study was intended to ascertain whether methiothepin pretreatment would induce behavioral serotonergic supersensitivity, as assayed by evaluating head-twitch response to quipazine and L-5-hydroxytryptophan (L-5HTP). Methiothepin-pretreated rats exhibited a significantly reduced response after quipazine but not a significant change after L-5HTP. Such findings could be explained by considering that quipazine stimulates both serotonin and dopamine receptors and by hypothesizing that methiothepin also induced dopaminergic supersensitivity which hampered head-twitch behavior. Such an explanation was supported by the following findings. Rats tested 5 days after a large dose of haloperidol exhibited reduced head-twitch response to quipazine. Moreover, rats which had received a single administration of either haloperidol or methiothepin showed (1) more sustained spontaneous locomotor activity, and (2) enhanced stereotyped response to apomorphine.

5-Hydroxytryptophan↗
PubMed1975

The mechanism by which methiothepin, a putative serotonin receptor antagonist, icnreses brain 5-hydroxyindole levels.

Brain tryptophan and 5-hydroxyindole levels are elevated in rats given methiothepin, a neuroleptic that appears to block serotonin receptors. The rise in brain tryptophan probably results from a drug-induced increase in the ratio of plasma tryptophan concentration to the sum of the neutral amino acids in plasma that compete with tryptophan for uptake into the brain; this change in the plasma amino acid pattern may be mediated in part by a methiothepin-induced rise in plasma insulin. Methiothepin also decreases the proportion of circulating tryptophan that is bound to albumin. Unlike exogenous tryptophan, methiothepin fails to increase 5-hydroxyin-doles caudal to the site of a spinal cord transection. Therefore, the mechanism by which methiothepin elevates 5-hydroxyindole levels involves not only increased brain tryptophan levels but also continued impulse flow along serotonergic neurons.

Amino Acids↗
PubMed1987

Methiothepin enhances the potassium-evoked release of [3H]-noradrenaline in rat pineal gland.

The 5-hydroxytryptamine (5-HT) autoreceptor antagonist methiothepin increased in a concentration-dependent manner the K+-evoked release of [3H]-noradrenaline in pineal glands from normal and parachlorophenylalanine (PCPA)-treated rats. However, 5-HT and the 5-HT receptor agonists, LSD and 5-methoxytryptamine, were inactive at modulating the K+-evoked release of [3H]-noradrenaline in pineal glands from normal and PCPA-treated rats. When tested on the uptake of [3H]-noradrenaline in the pineal gland, methiothepin was found to be a potent inhibitor (IC50 = 10.6 nmol/l). Exposure to methiothepin failed to increase the K+-evoked release of [3H]-noradrenaline when tested in the presence of cocaine. While the K+-evoked release of [3H]-noradrenaline was shown to be modulated through inhibitory presynaptic alpha 2-adrenoceptors in pineal glands from normal and PCPA-treated rats, no evidence was obtained for a presynaptic modulation through 5-HT receptors of [3H]-noradrenaline release. The facilitation by methiothepin of the K+-evoked release of [3H]-noradrenaline in rat pineal gland appears to be due to the inhibition of noradrenaline uptake by this compound.

Animals↗
PubMed1987

Methiothepin reduces glucose utilization in forebrain regions of awake rats.

Local cerebral glucose utilization (LCGU) was measured, using the quantitative autoradiographic [14C]2-deoxy-D-glucose method, in 92 discrete brain regions of awake rats, at 1, 2, 3, or 4 h after administration of the serotonergic antagonist methiothepin 0.1 mg/kg IP. The drug produced a cataleptic behavior that peaked in intensity at 3 h after its administration. LCGU declined significantly in 35% of the 92 regions at one or more time points after methiothepin administration. No area of increased metabolism was found. The time-course of the decline in LCGU closely paralleled the intensity of catalepsy; the peak effect was at 3 h, when LCGU was significantly reduced in 32% of the regions examined (mean decline for all regions was 15%). Metabolic depression after methiothepin was most notable in the forebrain, where LCGU declined in many regions of the cerebral cortex, basal ganglia, and thalamus. Most of the regions affected by methiothepin possess a substantial number of serotonin receptors, although LCGU was also reduced in a few regions not primarily involved in serotonergic neurotransmission.

Animals↗
PubMed1979

Studies on tryptophan accumulation in brain during methiothepin-induced enhancement of 5-hydroxyindole synthesis.

The elevation of brain tryptophan, 5-hydroxytryptophan and 5-hydroxyindoles (serotonin + 5-hydroxyindole acetic acid) that results from a tryptophan load is potentiated by prior administration of methiothepin, a serotonin receptor antagonist. Co-administration of valine with tryptophan attenuates these effects even in animals receiving methiothepin pretreatment. Administration of methiothepin and tryptophan to rats with widespread reduction of brain 5-hydroxyindole levels resulting from raphe lesions or 5,7-dihydroxytryptamine pretreatment still enabled brain tryptophan levels to rise considerably above the sum of increases found in animals receiving one or the other. Following transection of the spinal cord, the cranial portion still exhibited enhanced uptake of tryptophan and 5-hydroxyindole synthesis following methiothepin plus tryptophan treatment, however, both these events were absent in the caudal segment. Apparently, enhanced tryptophan uptake can proceed in the presence of minimal neuronal activity; however, when nerve impulse flow is eliminated, both 5-hydroxyindole synthesis and tryptophan uptake is impaired.

Amino Acids↗
PubMed1976

[Metabolism of methiothepin in the rat, dog and man].

Report is given on a metabolic investigation with non-radioactive and 14C-labelled methiothepin(1-[10',11'-dihydro-8'-(methylthio)-dibenzo mean value of b,f thiepin-10'yl]-4-methyl-piperazine) in rat, dog, and man. After i.p. and oral administration of the drug to the rat, the metabolites of methiothepin were excreted fecally. In the same species, a considerable biliary secretion of the compounds has been demonstrated. In dog and in man, excreted metabolites have been found both in urine and feces after oral application of the drug. The biotransformation of methiothepin within the species investigated proceeds via hydroxylation, sulfoxidation, O-methylation, N-demethylation, N-oxidation and formation of conjugates. The large number of metabolites is due to the various sites of action within the molecule, that are accessible to in vivo oxidation. Of a large number of isolated positionally isomeric compounds, merely the basal structures could be clarified. Possibly the mode of biotransformation to which methiothepin is subjected in the organism, proves determinant for the way of excretion. In the rat, all metabolites are hydroxylated and reach the intestinal tract as conjugates with the bile. In dog and man, however, non-hydroxylated, sulfoxidized metabolites were likewise found, which were excreted mainly renally in both species.

Administration, Oral↗
PubMed1986

Effects of MDL 72222 and methiothepin on carotid vascular responses to 5-hydroxytryptamine in the pig: evidence for the presence of "5-hydroxytryptamine1-like" receptors.

The present study concerns the effects of MDL 72222 (0.5 mg X kg-1, i.v.), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and methiothepin (1.0 mg X kg-1, i.v.), an antagonist of both 5-HT2 and "5-HT1-like" receptors, on the responses to local infusions of 5-HT (2.0 micrograms X kg-1 X min-1) on the total common carotid artery blood flow and its complete distribution in anaesthetized pigs. As reported earlier, more than 80% of the carotid blood bypassed the capillary circulation via cranial arteriovenous anastomoses, while approximately 15% and 2% was distributed to the extracerebral structures and brain, respectively. The total carotid blood flow did not change or was moderately reduced by 5-HT, but the amine consistently caused a 85% reduction in arteriovenous anastomotic blood flow and a 5-fold increase in blood flow to the extracerebral tissues, mainly the skin and ears. The colour of the skin and ears changed to bright pink. Complete recovery from the effects of 5-HT was observed once the infusion was stopped. MDL 72222 and methiothepin did not themselves affect carotid haemodynamics. The responses to 5-HT were not modified by MDL 72222 except that the reduction of the total carotid blood flow by 5-HT was augmented. In contrast, methiothepin almost completely abolished both the reduction of arteriovenous anastomotic blood flow and the increase in tissue blood flow following 5-HT-infusion. The colour of the skin and ears also did not become pink.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs.

We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

Animals↗
PubMed1977

Methiothepin and a 5-HT pathway to rat substantia nigra.

Methiothepin reduced both median-raphe evoked and exogenous 5-HT depression of single substantia nigra neurones. While this is compatible with a serotonin releasing pathway, additional interactions of methiothepin with exogenous dopamine suggest the need for further pharmacological confirmation.

Acetylcholine↗
PubMed1992

Serotonin-dependent cerebral activation: effects of methiothepin and other serotonergic antagonists.

In scopolamine-treated (5.0 mg/kg, s.c.) rats hippocampal rhythmical slow activity (RSA) and neocortical low voltage fast activity (LVFA) occur only in close correlation with head movements, spontaneous changes in posture, or locomotion (Type I behavior). Previous work indicates that such scopolamine-resistant RSA and LVFA are dependent on ascending serotonergic projections. A test of 9 serotonergic antagonists (methiothepin; ritanserin; ketanserin; pizotifen; mianserin; pirenperone; ICS-205-930; metoclopramide; methysergide) showed that methiothepin produces a partial reduction in RSA and LVFA in scopolamine-treated rats, while the other antagonists are completely inactive over a wide range of doses. It may be that serotonergic cerebral activation depends on both 5-HT1 and 5-HT2 receptors.

Animals↗
PubMed1986

In vivo voltammetry in the suprachiasmatic nucleus of the rat: effects of RU24969, methiothepin and ketanserin.

Differential pulse voltammetry was performed in the suprachiasmatic nucleus (SCN) of anaesthetised rats. Peripheral administration of RU24969 (10 mg/kg) a 5HT1 receptor agonist, decreased the size of the 5HIAA oxidation peak whereas it was increased by the non-selective 5HT receptor antagonist methiothepin (10 mg/kg). The effects of RU24969 were attenuated by methiothepin while the 5HT2 receptor antagonist ketanserin (5 mg/kg i.p.) did not affect the response to RU24969. The results suggest that in vivo 5HT release and metabolism in the SCN is probably under the influence of the 5HT1 receptor.

Animals↗
PubMed1978

Modification of the effects of LSD-25, d-amphetamine and tryptamine on electrically evoked responses in the visual system by methiothepin and octoclothepin.

LSD-25 (32 microgram/kg), d-amphetamine (3.2 mg/kg), and tryptamine (320 to 3200 microgram/kg) given intravenously depressed the response recorded in the visual cortex to electrical stimulation of the optic chiasm of the chloralose anesthetized cat. Relatively large doses of 1 mg/kg of the dibenzothiepin derivatives, methiothepin and octoclothepin, antagonized the depressant effects of both LSD-25 and tryptamine to a greater degree than d-amphetamine.

Animals↗
PubMed1975

Effects of iproniazid, chlorpromazine and methiothepin on DMT-induced changes in body temperature, pupillary dilatation, blood pressure and EEG in the rabbit.

The effects of i.v. N,N-dimethyltryptamine (DMT) were studied on arterial blood pressure, rectal temperature, pupil size and the electroencephalogram of the rabbit. DMT altered these parameters in a dose-related manner causing increased blood pressure, hyperthermia, pupilary mydriasis and activation of the electroencephalogram. Pretreatment with the monoamine oxidase inhibitor, iproniazid, prolonged the effects of DMT, while pretreatment with chlorpromazine or methiothepin attenuated these actions of DMT.

Animals↗