Pharmacological activation of the glucagon-like peptide-1 (GLP-1) receptor and inhibition of the cannabinoid CB1 receptor were found to reduce food intake and body weight in humans and animals. Since earlier studies revealed that endocannabinoids may interact with other neurotransmitters to affect feeding behavior, we have examined whether a stable GLP-1 agonist, exendin-4 and a CB1 receptor antagonist, AM 251, may reciprocally enhance their inhibitory effects on food consumption in the rat. Additionally, we have tested whether the blockade of the GLP-1 receptor by exendin (9-39) modifies AM 251-dependent effects on energy balance. In a dose-response study, male Wistar rats were injected intraperitoneally with either 1.5-6.0 μg/kg exendin-4, 0.5-2 mg/kg AM 251, 80-320 μg/kg exendin (9-39) or their vehicle and the daily food and water intake as well as body weight changes were monitored two days before and two days after the injection. Exendin-4 at a dose of 3.0 and 6.0 μg/kg and AM 251 at a dose 2 mg/kg decreased significantly 24-hour food intake and body weight. Therefore, in the next study, the effects of lower doses of exendin-4 (1.5 μg/kg) and AM 251 (1.0 mg/kg) administered alone or together on food consumption were compared. As opposed to being injected alone, the co-administration of the two resulted in a marked decrease in both daily food intake and body weight. Exendin (9-39) did not modify the suppressory effect of the highest AM 251 dose on food consumption. Apparently, the effect of AM 251 on the appetite is not mediated by GLP-1. The concomitant stimulation of GLP-1 receptor and blockade of CB1 receptor, however, may act synergistically to inhibit appetite in the rat.