Many atypical antipsychotic drugs cause weight gain, but the mechanism of this weight gain is unclear. To dissect the role of the dopamine D2 receptor (D2R), an important receptor in the pharmacology of antipsychotic drugs, we analyzed the effect of olanzapine, risperidone, and ziprasidone on changes in body weight and food intake in male wild-type (WT) and D2R knockout (D2R(-/-)) mice. The oral delivery of atypical antipsychotics, olanzapine (5 and 10 mg/kg), risperidone (0.1 and 1.0 mg/kg) and ziprasidone (10 and 20 mg/kg) in both strains mice for 2 weeks suppressed body weight gain, except for olanzapine treatment in D2R(-/-) mice. Olanzapine treatment suppressed body weight gain and decreased food intake in WT mice, but also reduced fat body mass and locomotor activity, whereas D2R(-/-) mice did not show these changes. Ziprasidone and risperidone treatment produced similar responses in WT and D2R(-/-) mice. These data suggest the involvement of D2R in the effect of olanzapine on metabolic regulation. Further studies are required to explore the implications of D2R activity in antipsychotic-mediated metabolic complications. (C) 2010 Elsevier Inc. All rights reserved.