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Benzodiazepine (BZD) anxiolytics, through their activation of the BZD-GABA receptor complex, display robust anxiolytic-like effects following systemic administration in both conditioned and non-conditioned behavioral procedures. The present results show that the GABAA agonists muscimol (0.5-1.0 mg/kg), THIP (2.5-10.0 mg/kg), and isoguvacine (25.0 mg/kg) as well as the GABA transaminase (GABA-T) inhibitor AOAA (aminooxyacetic acid; 5.0-20.0 mg/kg) following intraperitoneal administration exert anxiolytic-like activity of similar magnitude to that of diazepam in two non-conditioned procedures, namely the social interaction and the elevated plus maze tests. We have also extended our original findings that the anti-epileptic drug sodium valproate exerts an anxiolytic-like effect in the Geller conflict paradigm, to show this agent's robust activity in the social interaction and elevated plus maze tests following systemic administration (100-400 mg/kg). These results show that GABAergic agents that facilitate GABA transmission are effective following systemic administration in non-conditioned anxiety procedures and may indicate potential therapeutic efficacy in certain anxiety states.

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Dunn, R.W., and S. Fielding: Yohimbine-induced seizures in mice: A model predictive of potential anxiolytic and GABA-mimetic agents. Drug Dev. Res. 10:177-188, 1987.Yohimbine potentiation of lethality in mice has been used as a model for the prediction of antidepressant agents [Quinton, 19631. 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 CD5o (median convulsive dose) for yohimbine-induced seizures was 22.7 (18.9-27.3) mglkg sc (subcutaneously). For anticonvulsant screening, compounds were administered intraperitoneally at appropriate pretreatment times prior to the CDg5 dose of yohimbine (45 mglkg sc). The following anxiolytic and GABA-mimetic agents administered intraperitoneally dose-dependently antagonized yohimbine-induced clonic convulsions: diazepam (ED50 = 0.26 mglkg); chlordiazepoxide (2.0 mglkg); CGS 9896 (0.82 mglkg); CL 218,872 (3.7 mglkg); zopiclone (19.0 mglkg); tracazolate (61.3 mg/ kg); clonazepam (0.02 mg/kg); phenobarbital (9.0 mglkg); valproic acid (81.1 mglkg); trimethadione (163.0 mglkg); muscimol (0.82 mglkg); AOAA (16.0 mglkg); clonidine (0.22 mg/kg); and baclofen (4.0 mglkg). 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 (ED50 = 30.7 mglkg). 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