Clozapine promotes approach-oriented behavior in male mice.

Clozapine, an atypical antipsychotic agent, exerts ameliorative effects upon negative symptoms, but to date, its mechanism of action is poorly understood. We employed ethological methods to study the effects of clozapine, given 1 hour beforehand, on the social responses of (1) an individually housed male mouse exposed to an equally "matched" aggressive male opponent and (2) a group-housed "intruder" mouse exposed to an isolated, aggressive male. Encounters lasted 6 minutes. In matched pairs, mice given clozapine (0.01, 0.03, or 0.1 mg/kg s.c.) showed a significant increase in aggression without signs of stimulation. When given to intruder mice, clozapine (0.03, 0.1, or 0.3 mg/kg p.o.) markedly reduced defensive behavior and reinstated their investigative and sexual activities. The results suggest that low, nonsedating doses of clozapine counteract social withdrawal by selectively increasing "situationally appropriate" approach behavior.