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Yohimbine‐induced seizures in mice: A model predictive of potential anxiolytic and GABA‐mimetic agents
Author(s) -
Dunn Robert W.,
Fielding Stuart
Publication year - 1987
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430100306
Subject(s) - yohimbine , pharmacology , anxiolytic , anticonvulsant , anxiogenic , diazepam , chemistry , ethosuximide , buspirone , alprazolam , chlordiazepoxide , pentylenetetrazol , flumazenil , benzodiazepine , medicine , antagonist , epilepsy , agonist , anxiety , biochemistry , receptor , psychiatry
Yohimbine potentiation of lethality in mice has been used as a model for the prediction of antidepressant agent [Quinton, 1963]. However, prior to death or at sublethal doses, yohimbine induces clonic convulsions. In Swiss‐Webster mice (20–28 g) individually placed in clear plastic cylinders, the CD 50 (median convulsive dose) for yohimbine‐induced seizures was 22.7 (18.9−27.3) mg/kg sc (subcutaneously). For anticonvulsant screening, compounds were administered intraperitoneally at appropriate pretreatment times prior to the CD 95 dose of yohimbine (45 mg/kg sc). The following anxiolytic and GABA‐mimetic agents administered intraperitoneally dose‐dependently antagonized yohimbine‐induced clonic convulsions: diazepam (ED 50 ) = 0.26 mg/kg); chlordiazepoxide (2.0 mg/kg); CGS 9896 (0.82 mg/kg); CL 218,872 (3.7 mg/kg); zopiclone (19.0 mg/kg); tracazolate (61.3 mg/kg); clonazepam (0.02 mg/kg); phenobarbital (9.0 mg/kg); valproic acid (81.1 mg/kg); trimethadione (163.0 mg /kg); muscimol (0.82 mg/kg); AOAA (16.0 mg/kg); clonidine (0.22 mg/kg); and baclofen (4.0 mg/kg). On the other hand, the antiepileptic agents diphenylhydantoin, ethosuximide, and carbamazepine as well as the benzodiazepine antagonists CGS 8216 and RO 15 1788 were inactive. The neuroleptics haloperidol, chlorpromazine, and thioridazine were inactive, while clozapine displayed anticonvulsant activity (ED 50 = 30.4 mg/kg). Other inactive compounds include phenotolamine, propranolol, atropine, alpha‐methyltyrosine, PCPA, reserpine, buspirone, DMI, and imipramine. Since yohimbine has been reported to be anxiogenic in animals and man, this assay may be relevant for the prediction of anxiolytic agents. Furthermore, compounds active in this test have shown anxiolytic activity in behavioral conflict paradigms.