The role of CB₁ receptors in sweet versus fat reinforcement: Effect of CB₁ receptor deletion, CB₁ receptor antagonism (SR141716A) and CB₁ receptor agonism (CP-55940)

It is well established that Cannabis sativa can increase appetite, particularly for sweet and palatable foods. In laboratory animals, cannabinoid CB₁ receptor antagonism decreases motivation for palatable foods, and most recently, the CB₁ receptor antagonist SR141716A, or rimonabant (Acomplia), was reported to produce weight loss in obese human subjects. Indeed, the endocannabinoid system plays a select role in the rewarding properties of palatable foods, and this is well characterized in laboratory animals with sweet sucrose solutions. In the present study, CB₁ knockout mice (CB ₁ KO) and wild-type littermate mice (WT) were trained to respond for a complex sweet as well as a pure fat reinforcer under a progressive ratio (PR) schedule, to determine whether motivation to consume different palatable foods is tonically regulated by CB₁ receptors. To assess sweet reinforcement, several concentrations of the liquid nutritional drink, Ensure, were presented under the PR schedule. For fat reinforcement, several concentrations of corn oil (emulsified in 3% xanthan gum) were made available. Additionally, to compare the result of genetic invalidation of the CB ₁ receptor to antagonism of the CB₁ receptor system, the effect of SR141716A (3.0 mg/kg) on responding for Ensure and corn oil were also assessed using the PR schedule. We also assessed the effect of the CB ₁ agonist CP-55940 (30 μg/kg) on responding for Ensure and corn oil. CB₁ KOs took significantly longer to acquire operant responding maintained by Ensure, and responding for Ensure under the PR schedule was significantly reduced in CB₁ KOs as well as in WTs pretreated with SR141716A, as compared to WT controls. Additionally, pretreatment with the CB₁ agonist CP-55940 increased responding for Ensure. In contrast, responding for corn oil during acquisition and under the PR schedule was not significantly different in CB₁ KOs versus wild-type mice. However, SR141716A did reduce responding for corn oil in WTs, and CP-55940 significantly increased responding for corn oil. Taken together, these results suggest that CB₁ receptors are preferentially involved in the reinforcing effects of a complex sweet, as compared to a pure fat, reinforcer. These data also suggest, however, that antagonism of CB₁ receptors with SR141716A is sufficient to attenuate the reinforcing effect of Ensure and corn oil, while activation of the central CB₁ system is sufficient to enhance Ensure and corn oil reinforcement.