Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Methiothepin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

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↗
PubMed2006

Evaluation of the serotonin receptor blocker methiothepin in broilers injected intravenously with lipopolysaccharide and microparticles.

There has been considerable interest in the role of serotonin (5-hydroxytryptamine, 5-HT) in the pathogenesis of pulmonary hypertension due to episodes of primary pulmonary hypertension in humans linked to serotoninergic appetite-suppressant drugs. In this study, we investigated the effect of 5-HT on the development of pulmonary hypertension induced by injecting bacterial lipopolysaccharide (LPS; endotoxin) and cellulose microparticles intravenously, using the nonselective 5-HT(1/2)receptor, antagonist methiothepin. In Experiment 1, broilers selected for ascites susceptibility or resistance under conditions of hypobaric hypoxia were treated with methiothepin or saline, followed by injection of LPS, while recording pulmonary arterial pressure (PAP). In Experiment 2 ascites-susceptible broilers were treated with methiothepin or saline, followed by injection of cellulose microparticles, while recording PAP. In Experiment 3, an i.v. microparticle injection dose shown to cause 50% mortality was injected into ascites-susceptible and ascites-resistant broilers after methiothepin or saline treatment. Injecting methiothepin reduced PAP below baseline values in ascites-susceptible and ascites-resistant broilers, suggesting a role for 5-HT in maintaining the basal tone of the pulmonary vasculature in broilers. Injecting microparticles into the wing vein had no affect on the PAP in the broilers treated with methiothepin, suggesting that 5-HT is an important mediator in the pulmonary hypertensive response of broilers to microparticles. Furthermore, injecting an 50% lethal dose of microparticles into ascites-susceptible and ascites-resistant broilers pretreated with methiothepin resulted in reduced mortality. Serotonin appears to play a less prominent role in the pulmonary hypertensive response of broilers to intravenously injected LPS, indicating that other mediators within the innate response to inflammatory stimuli may also be involved. These results are consistent with our hypothesis that pulmonary hypertension syndrome ensues when vasoconstrictors, such as 5-HT, overwhelm the dilatory effects of vasodilators, such as NO, thereby effectively reducing the pulmonary vascular capacity of pulmonary hypertension syndrome-susceptible broilers.

Animals↗
PubMed2002

Methiothepin attenuates gastric secretion and motility effects of vagal stimulants at the dorsal vagal complex.

Methiothepin, a nonselective 5-HT receptor antagonist was utilized to explore the 5-HT modulation of dorsal vagal complex-TRH (thyrotropin releasing hormone) analogue stimulated gastric functional parameters. Intracisternal methiothepin pretreatment (200, 0.1 nmol) produced significant inhibition (70%, 44%, respectively) of the TRH analogue [p-Glu-His-(3,3'-dimethyl)-Pro NH2; RX 77368 (12 pmol)]-induced gastric acid output compared to vehicle pretreatment. Intracisternal pretreatment with methysergide (nonspecific 5-HT receptor antagonist) or combined cyanopindolol (5-HT(1A and 1B) receptor antagonist)+ritanserin (receptor antagonist of the 5-HT(2) family) did not alter the dorsal vagal complex-RX 77368 response. Unilateral dorsal vagal complex pretreatment with methiothepin (50 nmol/50 nl) attenuated ipsilateral dorsal vagal complex-TRH analog (12 pmol) induced gastric secretory response by 57%. The gastric secretagogue response to stimulation of the raphe obscurus (mediated by TRH release into the dorsal vagal complex) was inhibited 50% by pretreatment with intracisternal dorsal medullary methiothepin (0.1 nmol/10 microl). Intracisternal methiothepin (200 nmol/20 microl) also attenuated (a) dorsal vagal complex-glutamate (60 nmol/30 nl) stimulated gastric acid secretion and (b) gastric motility stimulated by dorsal vagal complex-RX 77368 (12 pmol/30 nl). The data suggest that other properties of methiothepin, alone or in addition to its 5-HT receptor antagonist effect, mediate its inhibitory actions at the dorsal vagal complex.

Animals↗
PubMed1984

Effects of methiothepin and lysergic acid diethylamide on serotonin release in vitro and serotonin synthesis in vivo: possible relation to serotonin autoreceptor function.

An in vitro system characterizing the presynaptic serotonin (5-HT) autoreceptor which controls the release of 5-HT from rat brain slices is described. Using this system, methiothepin (1-10 microM) demonstrated 5-HT autoreceptor antagonist activity by enhancing 5-HT release, while several recognized postsynaptic 5-HT receptor antagonists were inactive: mianserin, cinanserin, cyproheptadine, methysergide. The activity of methiothepin was highest in hypothalamic slices and lowest in striatal slices and was inhibited by the autoreceptor agonists lysergic acid diethylamide (LSD) and 5-methoxytryptamine (5-MT). The reversal of the methiothepin-enhanced 5-HT release from hypothalamic slices by LSD was not influenced by 0.3 microM tetrodotoxin. The peripheral administration of LSD to rats has been shown to reduce 5-HT synthesis and release by a mechanism thought to involve, in part, an autoreceptor-mediated reduction in impulse flow of 5-HT neurons. In the present experiments, intraperitoneal injection of methiothepin antagonized the LSD-induced reduction in hypothalamic 5-HT synthesis (5-hydroxytryptophan accumulation) while exerting no influence by itself. Conversely, compounds which were not active as 5-HT autoreceptor antagonists in vitro (i.e., cyproheptadine, methysergide, cinanserin) did not influence the effect of LSD on 5-HT synthesis. Further, the reduction in 5-hydroxytryptophan (5-HTP) accumulation by LSD showed regional differences in inhibition by methiothepin (hypothalamus greater than cortex greater than striatum) which paralleled the autoreceptor antagonist activity of methiothepin in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Effects of the serotonin receptor ligand methiothepin on reproductive behavior of the freshwater snail Biomphalaria glabrata: reduction of egg laying and induction of penile erection.

The biogenic monoamine serotonin (5-HT) has been reported to enhance egg laying in the freshwater gastropod Biomphalaria glabrata, an intermediate host for human blood flukes. Methiothepin, a vertebrate 5-HT(1/2) receptor ligand which binds with high affinity to a 5-HT receptor (5-HTlym) in Lymnaea stagnalis was tested for its ability to block egg laying in B. glabrata as a possible target for snail control. A single 30-min application of methiothepin (1 microM) was sufficient to prevent egg laying for over 1 week and did so in a dose-dependent fashion. Furthermore, single applications of methiothepin (1 microM and 10 microM) induced penile erection in a high percentage of snails tested. Latency to erection was long (at least 8 hr), but the duration of erection was long-lasting (up to 48 hr). Despite the erections, methiothepin-treated snails failed to achieve copulations. The pharmacological effect of methiothepin on both male and female reproductive processes is similar to that produced in other molluscs, and points to the gene for the 5-HT receptor mediating or modulating both or either processes as a potential target of snail control strategies. J. Exp. Zool. 289:202-207, 2001.

Animals↗
PubMed1982

Effect of methiothepin on imipramine- or mianserin- induced subsensitivity of serotonergic receptors.

Effect of methiothepin on imipramine- or mianserin- induced subsensitivity of serotonergic receptors was examined in rat brain. Treatment with either imipramine plus methiothepin or mianserin plus methiothepin for 4 days resulted in a significant decrease in [3H]5-hydroxytryptamine ([3H]5-HT) binding in synaptic membranes. The binding was not significantly decreased after treatment for this period of time with either methiothepin, imipramine or mianserin alone. It is suggested that the elevated intrasynaptic 5-HT levels could contribute to potentiation effect of methiothepin on imipramine- or mianserin-induced down regulation of serotonergic receptors.

Animals↗
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↗
PubMed2006

Evaluation of the serotonin receptor blockers ketanserin and methiothepin on the pulmonary hypertensive responses of broilers to intravenously infused serotonin.

The pathogenesis of pulmonary hypertension remains incompletely understood. Many factors have been implicated; however, there has been great interest in the potent pulmonary vasoconstrictor serotonin (5-HT) due to episodes of primary pulmonary hypertension in humans triggered by serotoninergic appetite-suppressant drugs. Pulmonary hypertensive patients have elevated blood 5-HT levels and pulmonary vasoconstriction induced by 5-HT is believed to be mediated through 5-HT1B/1D and 5-HT2A receptors that are expressed by pulmonary smooth muscle cells. The vascular remodeling associated with pulmonary hypertension also appears to require the serotonin transporter. We investigated the roles of 5-HT receptor blockers on the development of pulmonary hypertension induced by infusing 5-HT i.v. in broilers. For this purpose, we treated broilers with the selective 5-HT2A receptor antagonist ketanserin (5 mg/ kg of BW) or with the nonselective 5-HT1/2 receptor antagonist methiothepin (3 mg/kg of BW). Receptor blockade was followed by infusion of 5-HT while recording pulmonary arterial pressure and pulmonary arterial blood flow. The results demonstrate that methiothepin, but not ketanserin, eliminated the 5-HT-induced pulmonary hypertensive responses in broilers. The 5-HT2A receptor does not, therefore, appear to play a role in the 5-HT-induced pulmonary hypertensive responses in broilers. Methiothepin did not inhibit pulmonary vascular contractility per se, because the pulmonary hypertensive response to the thromboxane A2 mimetic U44069 remained intact in methiothepin-treated broilers. Methiothepin will be a useful tool for evaluating the role of 5-HT in the pathogenesis of pulmonary hypertension syndrome (ascites) as well as the onset of pulmonary hypertension triggered by inflammatory stimuli such as bacterial lipolysaccharide.

Animals↗
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↗
PubMed2006

Methiothepin-sensitive serotonin receptors are involved in the postsynaptic mechanism of sensitization of the defensive response in the common snail.

Rhythmic electrical stimulation of the snail foot leads to sensitization of the defensive reflex. This sensitization has dynamics similar to those of posttetanic potentiation of the amplitude of the acetylcholine-evoked influx current of defensive behavior command neurons in the common snail. It is likely that an increase in the cholinosensitivity of the somatic membrane of defensive behavior command neurons in the common snail may be involved in the mechanism of sensitization of the animal's defensive response. Methiothepin, an antagonist of serotonin receptors, prevented the posttetanic potentiation of the acetylcholine-evoked influx current as well as behavioral sensitization. Serotonin, like methiothepin, also impaired posttetanic potentiation of the acetylcholine-evoked influx current. It is suggested that methiothepin-sensitive serotonin receptors are involved in the postsynaptic mechanism of behavioral sensitization.

Acetylcholine↗
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↗