title: Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.
abstract: Nicotine, the main psychoactive component of tobacco, and (-)-Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Schindler
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.affiliation: Center for Drug Discovery, Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Vemuri
authors.affiliation: Center for Drug Discovery, Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.|Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
authors.affiliation: Preclinical Pharmacology Program, McLean Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Bergman
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D013759:Dronabinol / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008297:Male; D002189:Marijuana Abuse / Q000517:prevention & control; D009538:Nicotine / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012008:Recurrence; D012054:Reinforcement, Psychology; D000077285:Rimonabant; D012453:Saimiri; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000517:prevention & control
chemical_list: C529765:AM4113; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D009538:Nicotine; D013759:Dronabinol; D000077285:Rimonabant