It is well established that treatment with rimonabant, a CB 1 antagonist, decreases food intake and body weight gain. In part, these responses are mediated by increased activity of hypothalamic neurons related with energy homeostasis. However, food consumption is reversed to basal level during prolonged CB 1 antagonist treatment, suggesting tolerance to its anorexigenic effect. This study investigated the effects of acute or prolonged CB 1 receptor blockade on the expression of hypothalamic neuropeptides involved with energy homeostasis. Male Wistar rats received vehicle, a single dose or daily doses of rimonabant (10mg/kg by gavage) over 7days. Food intake, body weight, CRF and CART immunoreactivity, as well as, mRNA expression of hypothalamic neuropeptides were evaluated. In comparison with vehicle treatment, single dose of rimonabant decreased food intake and body weight. Acute rimonabant treatment also increased Fos-CRF and Fos-CART double labeled neurons in the PVN and Fos immunoreactivity in the ARC. We also observed that acute rimonabant treatment increased CRF, CART and TRH mRNA expression in the PVN, while it decreased POMC and NPY mRNA expression in the ARC with no changes in the CART mRNA expression in this nucleus. There was an increase in CB 1 mRNA expression in the PVN of rats that received both acute and prolonged-rimonabant treatment. Interestingly, rats subjected to prolonged rimonabant treatment had no changes in food intake, body weight gain, hypothalamic mRNA expression, Fos expression and CRF and CART neuron activation. These data indicate that tolerance to hypophagic effects of CB 1 antagonist, rimonabant, is associated with reversion of hypothalamic neuropeptide gene expression related to regulation of energy homeostasis.