zimeldine and 1-(3-chlorophenyl)piperazine

In this study, the elevated zero-maze model of anxiety was used to investigate CCK receptor antagonist effects on the behaviour of male Lister-hooded rats and to demonstrate, by administering antagonists in the presence or absence of selective 5-hydroxytryptamine (5-HT) re-uptake inhibitors, the involvement of 5-HT in the mediation of these effects. Devazepide, a selective CCKA receptor antagonist, L-365,260 (3R(+)-N-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin- 3-yl-N1- (3-methyl-phenyl)urea) or CI-988 (4-([2-[[3-(1H-indol-3-yl)-2-methyl-1- oxo-2-[[(tricyclo[3.3.1.1.(3.7)]-dec-2-yloxy)-carbonyl]-amin o]- propyl]-amino]-1-phenylethyl]-amino)-4-oxo-[R-(R*,R*)]-butanoate- N-methyl-D-glucamine), both selective CCKB receptor antagonists, were administered 30 min prior to testing. Behavioural analysis during testing included measures of risk-assessment behaviours (e.g. stretched-attend posture) in addition to time spent on the open quadrants. Devazepide induced significant anxiolytic effects, whereas CI-988 produced inconsistent results and L-365,260 was ineffective. When administered simultaneously with the 5-HT re-uptake inhibitors zimelidine or Wy 27587 (N-[[[1-[(6- fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino] carbonyl]-3-pyridine carboxamide methyl sulphonate salt), the significant anxiolytic effect induced by devazepide was dose-dependently and significantly attenuated. Zimelidine and Wy27587 had little effect alone on zero-maze behaviour at the lower of two doses given. These data show that the elevated zero-maze, in conjunction with the analysis of 'risk-assessment' behaviours, is an anxiety model which is sensitive to the anxiolytic effects of CCK receptor antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Anxiety Agents; Benzodiazepinones; Devazepide; Diazepam; Indoles; Male; Maze Learning; Meglumine; Niacinamide; Phenylurea Compounds; Piperazines; Piperidines; Rats; Receptors, Cholecystokinin; Selective Serotonin Reuptake Inhibitors; Zimeldine

1. The effects of 5-hydroxytryptamine (5-HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble-burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway were used as a separate test of non-specific drug effects. 2. Fluvoxamine, zimeldine, indalpine and citalopram dose-dependently inhibited burying without affecting runway activity. 5-Hydroxytryptophan (5-HTP, with carbidopa), 5-methoxy-N,N-dimethyltryptamine, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), buspirione, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 1,-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-(3-chlorophenyl)-piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity. 3. 5-HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169,369 and cyproheptadine but not by pindolol or a low (0.25 mg kg-1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg-1. 4. Zimeldine burying inhibition was potentiated by ritanserine, ICI 169,369, ICS 205-930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations. 5. Zimeldine was administered in drinking water at a dose of 10 mg kg-1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48h after withdrawal at which times responses to DOI were at control levels.6. Selective inhibition of marble burying was not found to be a property of 5-HT-related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5-HT uptake inhibitors and 5-HT releasing agents; this generality suggests that elevated synaptic 5-HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5-HT2 receptor but those of the 5-HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5-HT receptor subtype. This, together with the potentiating effect of several 5-HT antagonists on the response to zimeldine, raises th

Topics: 5-Hydroxytryptophan; Amphetamines; Animals; Anti-Anxiety Agents; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Female; Fenfluramine; Fluvoxamine; Mice; Motor Activity; Piperazines; Serotonin; Serotonin Antagonists; Zimeldine

The mechanism of action of 5-hydroxytryptophan (5-HT, 10 mg/kg), quipazin (7 mg/kg), zimelidin (15 mg/kg) and m-chlorophenylpiperazine (5 mg/kg) was examined with the aid of some analyzer substances. The avoidance behavior under stress was used as criterion of estimation. The optimizing effect of 5-HT on the avoidance behavior was demonstrated to be a consequence of serotonin synthesis activation and its release with activation of postsynaptic 5-HT-1-receptors. An adverse effect of quipazin on the avoidance behavior was, to a greater degree, due to the activation of 5-HT-2-autoreceptors rather than of dopamine receptors. The inhibitory effect of m- chlorphenylpiperazine was reversed by administration of pyrenepyrone , a blocker of 5-HT-2-receptors. The inhibitory effect of zimelidine on the avoidance behavior was not removed by clonidin . The positive effect on the avoidance behavior under stress occurs as a result of exposures that activate the synthesis and release of 5-HT as well as of activation of postsynaptic 5-HT-1 receptors.

Topics: 5-Hydroxytryptophan; Acute Disease; Animals; Avoidance Learning; Cyproheptadine; Humans; Hydrazines; Male; Piperazines; Piperidines; Quinolines; Quipazine; Rats; Rats, Inbred Strains; Stress, Psychological; Tranquilizing Agents; Zimeldine

The data are provided on the effect of some serotoninergic substances on the avoidance behavior under acute stress. 5-Hydroxytryptophan, zimelidine (low doses), pyrenepyron, ciproheptadine, trazodon (high doses), produced a noticeable positive action on the behavior pattern under study. Quipazin and zimelidine (high doses) provoked an increase in the number of affective manifestations and a rise of the latent avoidance time. Regardless of an appreciable fall in the number of affective manifestations, the powerful sedative effect of m-chlorphenylpiperazine led to an increase in the latent response periods. It was shown that substances that produced a direct or mediated activation effect on the serotoninergic system had an appreciable favourable influence on the avoidance behavior, which was a consequence of a decrease in the animals' emotional excitement. Combination of serotonin-blocking properties (action on S2-autoreceptors) and dopaminergic properties brought about optimal results, provided that pyrenepyron was applied.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents; Brompheniramine; Cyproheptadine; Escape Reaction; Humans; Male; Piperazines; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Stress, Psychological; Tranquilizing Agents; Trazodone; Zimeldine