Abstract
Nicotine, the main psychoactive component of tobacco, and (−)−Δ9-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.
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Acknowledgements
This study is dedicated to the memory of Dr Steven R Goldberg (died on 25 November 2014). AM4113 was provided by Dr Alexandros Makriyannis. Rimonabant was provided by NIDA Drug Supply Program (Bethesda, MD). We thank Dr Ira Baum and Philip White for their excellent veterinary assistance during the study. This work was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, by NIDA grants R01DA19205, R01DA31020 (to Jack Bergman), and P01DA009158, R01DA007215, R37DA023142, and R37DA003801 (to Alexandros Makriyannis).
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Schindler, C., Redhi, G., Vemuri, K. et al. Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys. Neuropsychopharmacol 41, 2283–2293 (2016). https://doi.org/10.1038/npp.2016.27
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DOI: https://doi.org/10.1038/npp.2016.27
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