Preclinical anxiolytic versus antipsychotic profiles of the 5‐HT3 antagonists ondansetron, zacopride, 3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester, and 1αH, 3α, 5αH‐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 (3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester; 0.5 and 1.0 mg/kg), and MDL 72222 (1αH, 3α, 5αH‐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.