Perspectives in Pharmacology Cannabinoid CB1 Receptor Antagonists as Promising New Medications for Drug Dependence

This review examines the development of cannabinoid CB1 receptor antagonists as a new class of therapeutic agents for drug addiction. Abused drugs [alcohol, opiates, -tetrahydrocannabinol ( -THC), and psychostimulants, including nicotine] elicit a variety of chronically relapsing disorders by interacting with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems, and virtually all abused drugs elevate dopamine levels in the nucleus accumbens. Cannabinoid CB1 receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of -THC and nicotine. Rimonabant (SR141716), a CB1 receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of -THC in animals. Blockade of CB1 receptor activity by genetic invalidation also decreases rewarding effects of opiates and alcohol in animals. Although CB1 receptor blockade is generally ineffective in reducing the self-administration of cocaine in rodents and primates, it reduces the reinstatement of extinguished cocaine-seeking behavior produced by cocaine-associated conditioned stimuli and cocainepriming injections. Likewise, CB1 receptor blockade is effective in reducing nicotine-seeking behavior induced by re-exposure to nicotine-associated stimuli. Some of these findings have been recently validated in humans. In clinical trials, Rimonabant blocks the subjective effects of -THC in humans and prevents relapse to smoking in exsmokers. Findings from both clinical and preclinical studies suggest that ligands blocking CB1 receptors offer a novel approach for patients suffering from drug dependence that may be efficacious across different classes of abused drugs. CB1 Receptors Modulate the Brain Reward Pathway Drug dependence is a chronic, relapsing disorder in which compulsive drug-seeking and -taking behavior persists despite serious negative consequences (American Psychiatric Association, 2000). Addictive substances, such as cannabinoids, opioids, ethanol, and psychostimulants, including nicotine, induce pleasant states or relieve distress, effects that contribute to their recreational use. After repeated exposure, adaptive changes occur in the central nervous system that lead to drug dependence (American Psychiatric Association, 2000). Although addictive drugs produce their effects through actions at various receptors in the brain, it is thought that their common effects on the activity of dopaminergic brain reward pathways is primarily responsible for their addictive properties (Koob, 1992a,b; Wise, 2004). Notably, the mesocorticolimbic system, which projects from the ventral tegmental area to the nucleus accumbens, cortical areas, and amygdala, is implicated in the rewarding effects of psychostimulants and other drugs of abuse, as well as the effects of nondrug natural rewards such as food (Wise, 1982). The involvement of dopamine in the rewarding effects of drugs of abuse is suggested by findings that most drugs abused by humans increase levels of dopamine in the nucleus This study was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health, Department of Health and Human Services. B.L.F. is a visiting fellow at the NIDA, and his move to the NIDA was supported by the Gilbert Lagrue Foundation and Simone and Cino del Duca Foundation. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.077974. ABBREVIATIONS: -THC, -tetrahydrocannabinol; SR141716, Rimonabant; CPP, conditioned place preference(s); FR, fixed ratio; HU-210, (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol; AM-251, N-(piperidin-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide. 0022-3565/05/3123-875–883 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 312, No. 3 U.S. Government work not protected by U.S. copyright 77974/1192074 JPET 312:875–883, 2005 Printed in U.S.A.