There are numerous preclinical screening procedures that are predictive of clinical efficacy for the positive symptoms of schizophrenia but no assays for the negative symptoms such as social withdrawal. In the social interaction test in rats, the atypical antipsychotic drug clozapine (10.0 mg/kg) and two putative atypical agents risperidone (0.0625 mg/kg) and HP 873 (0.5 and 1.0 mg/kg) significantly increased social interaction behaviors between pairs of unfamiliar but not familiar rats. The benzodiazepine diazepam (1.25-5.0 mg/kg) increased social behaviors in both paradigms. Haloperidol, chlorpromazine, raclopride, and SCH23390 decreased social behaviors in these assays. In vitro receptor binding studies revealed that only clozapine, risperidone, and HP 873 displayed dopamine to serotonin affinity ratios for both D2/5-hydroxytryptamine2(5-HT2)/ and D1/5-HT1A of greater than or equal to 12.9 and 1.0, respectively. The present study suggests that antipsychotic agents that may be effective in social withdrawal can be identified in this modified social interaction paradigm. Further, our data suggests that a compound's effectiveness for the treatment of social withdrawal is at least in part due to its relative affinity for binding to dopamine D1 and serotonin 5-HT1A receptors.