PRECLINICAL ANXIOLYTIC VERSUS ANTIPSYCHOTIC PROFILES OF THE 5-HT3 ANTAGONISTS ONDANSETRON, ZACOPRIDE, 3-ALPHA-TROPANYL-1H-INDOLE-3-CARBOXYLIC ACID ESTER, AND 1-ALPHA-H, 3-ALPHA, 5-ALPHA-H-TROPAN-3-YL-3,5-DICHLOROBENZOATE

In preclinical studies, the behavioral effects of serotonin antagonists at 5-HT3 receptor sites suggest potential efficacy in the treatment of anxiety and schizophrenia. The present study shows that 5-HT3 antagonists were effective in disinhibiting behavior in non-conditioned rodent models which elicit a behavioral state presumed to be analogous to anxiety, but were generally not effective in conditioned rodent anxiety models or in assays that are traditionally predictive of antipsychotic agents. Ondansetron (0.01-0.1 mg/kg), zacopride (0.1-1.0 mg/kg), ICS 205-930 (3-alpha-tropanylH-indole-3-carboxylic acid ester; 0.5 and 1.0 mg/kg), and MDL 72222 (1-alpha-H, 3-alpha, 5-alpha-H-tropan-3-yl-3,5-dichlorobenzoate; 10.0 and 20.0 mg/kg) demonstrated anxiolytic effects in the social interaction and elevated plus maze procedures, while having little or no effect in a modified Cook and Davidson conflict procedure. Ondansetron, zacopride, and ICS 205-930 had no effect in neuroleptic screening procedures, such as the apomorphine climbing mouse assay (CMA), the pole climb avoidance (PCA) procedure, and the intracranial self-stimulation of the medial forebrain bundle (ICSS-MFB) assay. MDL 72222 had no effect on CMA but dose-dependently antagonized PCA (ED50 = 10.9 mg/kg) and ICSS-MFB (ED50 = 8.8 mg/kg). The results of the present study suggest that MDL 72222 possesses a profile of activity that is different from the other 5-HT3 antagonists tested and that, in general, 5-HT3 antagonists may prove to be efficacious in the treatment of certain forms of anxiety in man.