Serotonin and α1 adrenergic receptor antagonism may contribute to atypical antipsychotic drug effects. Clozapine (2.5 mg/kg) drug discrimination in C57BL/6 mice may selectively screen atypical antipsychotic drugs. Previous data show that the atypical antipsychotics olanzapine, risperidone, ziprasidone but not the typical antipsychotic haloperidol fully substitutes for clozapine. The present study demonstrated that the atypical antipsychotics quetiapine, sertindole, zotepine, iloperidone, melperone fully substituted for clozapine but aripiprazole did not. The typical antipsychotics fluphenazine and perphenazine failed to fully substitute for clozapine but chlorpromazine and thioridazine fully substituted for clozapine. This model does not differentiate between atypical and typical antipsychotic drugs but it may be useful in the detection of antipsychotics with potent serotonin and α1 adrenergic receptor antagonist actions.