Psychopathological disorders, and depression in particular, are strongly linked to eating attitude in obese patients. The identification of cannabinoid CB1 receptors (CB1Rs) in areas of the central nervous system (CNS) that have been implicated in regulation of mood and food intake suggests that these receptors may mediate such a behavioral link. The goal of this study was to evaluate CB1R modulation of antidepressant-like effects and food intake. For this purpose, 129/SVE and C57BL/6 male mice were acutely dosed intraperitoneally (i.p.) with the CB1R inverse agonist AM251 (3-30 mg/kg) and tested, respectively, in the tail-suspension test (TST) and in the forced-swim test (FST), which have been used widely as tests sensitive to antidepressant compounds. Like the antidepressant desipramine (DMI, 16 mg/kg), AM251 significantly reduced immobility at 10 mg/kg in the TST and at 1 and 10 mg/kg in the FST. Such a decrease of immobility was not accompanied by an increase in motor activity in the open field, suggesting that occupancy of CB1R by AM251 induced antidepressant-like effects. This was supported by two additional experiments. First, the co-administration of the CB1R agonist CP55940, at a dose that did not induce motor impairment or profound hypothermia (0.01 mg/kg), reversed effects of AM251 in the TST. Secondly, effects of AM251 in the FST were absent in CB1R knockout (KO) mice. In addition to an antidepressant-like effect, AM251 reduced fasting-induced hyperphagia over a comparable dose range. Taken together, these data suggest that regulation of mood and food intake might be obtained through inverse agonism of CB1R.