We studied the effects of perospirone (SM-9018), a novel serotonin-2 (5-HT2) and dopamine-2 (D2) receptor antagonist (SDA), on conditioned fear stress (CFS)-induced freezing behavior in rats and compared its actions with those of other antipsychotics. Exposure of rats to the environment previously paired with foot shock induced marked freezing behavior, which was reduced by the anxiolytic diazepam (0.1-3 mg/kg, p.o.) or antidepressants, desipramine and imipramine (10-100 mg/kg, p.o.). Perospirone at 0.3-3 mg/kg, p.o. significantly attenuated the CFS-induced freezing behavior in a dose-dependent manner, while the effect was reduced at the higher dose of 6 mg/kg. Other SDA-type antipsychotics, clozapine (1-30 mg/kg, p.o.) and risperidone (0.03-1 mg/kg, p.o.), and selective 5-HT2 antagonists, ritanserin (0.1-1 mg/kg, p.o.) and ketanserin (0.3-1 mg/kg, p.o.), all reduced the freezing behavior with U-shaped dose-response curves. However, neither conventional antipsychotic, haloperidol (0.1-3 mg/kg, p.o.), chlorpromazine (3-100 mg/kg, p.o.), thioridazine (3-100 mg/kg, p.o.), mosapramine (3-100 mg/kg, p.o.) nor tiapride (30-1000 mg/kg, p.o.) reduced the CFS-induced freezing behavior. In addition, subacute treatment of rats with perospirone (1-10 mg/kg/day) or imipramine (30 mg/kg/day) for 2 weeks prevented the induction of the freezing behavior by CFS. These findings suggest that SDA-type antipsychotics including perospirone are effective for the treatment of mood disturbances such as anxiety and depressive mood associated with schizophrenia and have a broader efficacy profile as compared with the conventional antipsychotics.