Effects of glucagon-like peptide-1 receptor stimulation and blockade on food consumption and body weight in rats treated with a cannabinoid CB1 receptor agonist WIN 55,212-2

BACKGROUND Glucagon-like peptide-1 (GLP-1) and endocannabinoids are involved in appetite control. Recently we have demonstrated that cannabinoid (CB)1 receptor antagonist and GLP-1 receptor agonist synergistically suppress food intake in the rat. The aim of the present study was to determine the effects of GLP-1 receptor stimulation or blockade on feeding behavior in rats treated with WIN 55,212-2, a CB1 receptor agonist. MATERIAL/METHODS Experiments were performed on adult male Wistar rats. In the first experiment the effects of increasing doses (0.5-4.0 mg/kg) of WIN 55,212-2 injected intraperitoneally on 24-hour food consumption were tested. In further experiments a GLP-1 receptor antagonist, exendin (9-39), and WIN 55,212-2 or a GLP-1 receptor agonist, exendin-4, and WIN 55,212-2 were injected intraperitoneally at subthreshold doses (that alone did not change food intake and body weight) to investigate whether these agents may interact to affect food intake in rats. RESULTS WIN 55,212-2 administered at low doses (0.5-2 mg/kg) did not markedly change 24-hour food consumption; however, at the highest dose, daily food intake was inhibited. Combined administration of WIN 55,212-2 and exendin (9-39) did not change the amount of food consumed compared to either the control group or to each agent injected alone. Combined injection of WIN 55,212-2 and exendin-4 at subthreshold doses resulted in a significant decrease in food intake and body weight in rats. CONCLUSIONS Stimulation of the peripheral CB1 receptor by its agonist WIN 55,212-2 can induce anorexigenic effects or potentiate, even at a subthreshold dose, the effects of exendin-4, a known anorectic agent. Hence, this dual action of the cannabinoid system should be considered in the medical use of CB1 agonists.