Drugs that interfere with
cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as
appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce
nausea and malaise. The present studies were undertaken to characterize the behavioral effects of
AM4113, which is a CB1 neutral antagonist, and to examine whether this
drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that
AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on
cyclic-AMP production). In tests of spontaneous locomotion and
analgesia,
AM4113 reversed the effects of the CB1 agonist AM411.
AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dose-dependent manner, and also suppressed feeding on high-fat, high-
carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding,
AM4113 did not induce conditioned gaping, which is a sign of
nausea and food-related malaise in rats. These results suggest that
AM4113 may decrease appetite by blocking endogenous
cannabinoid tone, and that this
drug may be less associated with
nausea than CB1 inverse agonists.