As revealed by previous microdialysis studies, basal and food intake-accompanied dopamine release significantly differs in the hypothalamus of obese vs. lean Zucker rats. In the present study, we determined whether dopaminergic receptors are also compromised in obesity. Dopaminergic D₁ and D₂ receptor mRNA expression was studied in the ventromedial hypothalamus (VMH), lateral hypothalamic area (LHA), and the adenohypophysis (AH) of obese and lean Zucker rats using RT-PCR technique. In obese Zucker rats, we found an upregulation of D₁ receptor mRNA in the VMH and AH and a downregulation in the LHA, whereas D₂ receptor mRNA was downregulated in both the VMH and LHA, but not changed in the AH, compared with lean rats. Also, an increase of D₁ receptor staining was seen in the paraventricular nucleus of obese rats by immunohistochemistry. We selected the VMH to test if the observed changes in the dopamine receptor expression of obese rats induce behavioral sensitization to dopamine as expressed by hyperphagia. The overnight food-deprived rats received a single VMH injection (10 nmol) of sulpiride (D₂ receptor antagonist) or saline as control, then food was provided and 1-h food intake was measured. Food intake after sulpiride vs. saline injection was greater in obese rats but was not different in lean rats. Our data suggest that downregulation of D₂ receptor in the hypothalamus at least in the VMH induces behavior sensitization for having large meals. Low D₂ receptor expression may be causal for an exaggerated dopamine release observed in obese rats during food ingestion and for reduced satiety feedback effect of dopamine. High level of D₁ receptor expression in the VMH and low in the LHA may also contribute to the specific feeding pattern in obese rats represented by large meal size and low meal number.