Effects of typical and atypical antipsychotic drugs on freezing behavior induced by conditioned fear

A typical antipsychotic drugs (atypical APDs), such as clozapine, ORG5222, and olanzapine, have been suggested to possess anxiolytic activity in the conflict test and elevated plus-maze test, while several studies have suggested that typical APDs are not anxiolytic in several models of anxiety. We investigated the effects of typical and atypical APDs on the acquisition and expression of conditioned fear-induced freezing. Drugs were administered subcutaneously to male Sprague-Dawley rats 30 min before foot shock stress (the VI60s schedule, 2.5 mA for 30 min). Twenty-four hours after foot shock, freezing behavior of rats was observed in the shock chamber without shocks. The atypical APD clozapine (0.3-10 mg/kg) dose-dependently inhibited the acquisition of conditioned freezing. Candidates for atypical APDs, ORG5222 (0.1-1 mg/kg), olanzapine (1-10 mg/kg), and raclopride (3-30 mg/kg), also reduced the acquisition of conditioned freezing in a dose-dependent manner. Typical APDs, haloperidol (3 mg/kg), spiperone (0.1-1 mg/kg) and nemonapride (1 mg/kg) had significant inhibitory effects on the acquisition of conditioned freezing, but their effects were reduced at higher doses. Chlorpromazine, a typical APD, showed about 50% inhibition of the acquisition of conditioned freezing at the dose of 10 mg/kg, but did not reveal significant inhibition at any of the doses (3-30 mg/kg). The ED50S (mg/kg) for inhibiting the acquisition of conditioned freezing significantly correlated with the Ki values for D4 dopaminergic receptors, but not with the Ki values for other monoamine and acetylcholine receptors. On the other hand, clozapine or haloperidol did not change the expression of conditioned freezing. These results suggest that protective effects of clozapine and other antipsychotic drugs on the acquisition of conditioned freezing may be mediated by blockade of D4 receptors.