The neutral cannabinoid CB₁ receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat.

The aim of this study was to determine if the neutral cannabinoid CB₁ receptor antagonist, AM4113, regulates body weight in the rat via changes in food intake. We confirmed that the AM4113-induced reduction in food intake is mediated by CB₁ receptors using CB₁ receptor knockout mice. In rats, intraperitoneally administered AM4113 (2, 10 mg kg⁻¹) had a transient inhibitory effect on food intake, while body weight gain was suppressed for the duration of the study. AM4113-induced hypophagia was no longer observed once the inhibitory effect of AM4113 on body weight stabilized, at which time rats gained weight at a similar rate to vehicle-treated animals, yet at a lower magnitude. Pair-feeding produced similar effects to treatment with AM4113. Food intake and body weight gain were also inhibited in rats by oral administration of AM4113 (50 mg kg⁻¹). Dual energy x-ray absorptiometry (DEXA) was used to measure lean and fat mass. The AM4113 treated group had 29.3±11.4% lower fat mass than vehicle-treated rats; this trend did not reach statistical significance. There were no differences in circulating levels of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG), glucose, triglycerides, or cholesterol observed between treatment groups. Similarly, 2-AG hypothalamic levels were not modified by AM4113 treatment. These data suggest that blockade of an endocannabinoid tone acting at CB₁ receptors induces an initial, transient reduction in food intake which results in long-term reduction of body weight gain.