Cannabinoid Cb1 Receptor Antagonists/Inverse Agonists and Food-Seeking Behavior

Abstract

For the last few years, drugs that interfere with cannabinoid CB1 receptor transmission have been assessed for their potential utility as appetite suppressants. CB1 antagonists and inverse agonists have been shown to suppress a number of food-related behaviors, including food-reinforced behaviors. In addition to rimonabant (SR141716A), several other compounds have been evaluated, including AM251, AM1387, AM4113, and AM6545. Based upon biochemical studies of signal transduction, it appears that most of the drugs assessed thus far have been CB1 inverse agonists. CB1 receptor inverse agonists such as rimonabant act to suppress food intake and disrupt food-reinforced behavior. Furthermore, CB1 receptor inverse agonists do not appear to produce severe motor impairments that disrupt feeding behavior. However, there is evidence that they can induce nausea and malaise, and also can increase signs of anxiety and depression. Because of these problems, recent studies have been undertaken to characterize the behavioral effects of CB1 receptor neutral antagonists such as AM4113 to determine if these drugs can reduce feeding and food-reinforced behaviors. Neither the neutral antagonist AM4113 nor the inverse agonist AM251 produces effects that closely resemble those of dopamine antagonists. Across a variety of different tests, AM4113 affects food-motivated behavior in ways that are very similar to the effects of CB1 inverse agonists. In addition, AM4113 did not induce conditioned gaping in rats or vomiting in ferrets, and did not produce an anxiogenic effect in the elevated plus maze. These results suggest that CB1 receptor neutral antagonists may decrease appetite by blocking endogenous cannabinoid tone, and that these drugs may be less associated with aversive effects than is the case for CB1 inverse agonists. Additional studies also have focused upon the potential peripheral effects of drugs that to interfere with CB1 transmission. Therefore, despite some current difficulties with the potential use of CB1 receptor inverse agonists for the treatment of obesity, it is possible that neutral antagonists, or drugs that have actions primarily on the periphery, could ultimately be useful for clinical assessment as appetite suppressants.