Peripheral and central leptin administration has been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R binding differences contribute to the phenotypic behaviors of leptin deficient ob/ob mice and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Striatal basal D2R binding (measured with autoradiography [ 3 H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice leptin decreased striatal D2R binding whereas in ob/ob mice leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2 receptor expression in striatum and that these effects are genotype/phenotype dependent.