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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cannabinoid CB1 Receptor Antagonists as Promising New Medications for Drug Dependence

Bernard Le Foll and Steven R. Goldberg
Journal of Pharmacology and Experimental Therapeutics March 2005, 312 (3) 875-883; DOI: https://doi.org/10.1124/jpet.104.077974
Bernard Le Foll
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Steven R. Goldberg
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Abstract

This review examines the development of cannabinoid CB1 receptor antagonists as a new class of therapeutic agents for drug addiction. Abused drugs [alcohol, opiates, Δ9-tetrahydrocannabinol (Δ9-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 Δ9-THC and nicotine. Rimonabant (SR141716), a CB1 receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of Δ9-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 cocaine-priming 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 Δ9-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.

Footnotes

  • 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.

  • doi:10.1124/jpet.104.077974.

  • ABBREVIATIONS: Δ9-THC, Δ9-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-(piperidinyl)-1-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.

    • Received September 15, 2004.
    • Accepted October 27, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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In this issue

Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cannabinoid CB1 Receptor Antagonists as Promising New Medications for Drug Dependence

Bernard Le Foll and Steven R. Goldberg
Journal of Pharmacology and Experimental Therapeutics March 1, 2005, 312 (3) 875-883; DOI: https://doi.org/10.1124/jpet.104.077974

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cannabinoid CB1 Receptor Antagonists as Promising New Medications for Drug Dependence

Bernard Le Foll and Steven R. Goldberg
Journal of Pharmacology and Experimental Therapeutics March 1, 2005, 312 (3) 875-883; DOI: https://doi.org/10.1124/jpet.104.077974
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    • Abstract
    • CB1 Receptors Modulate the Brain Reward Pathway
    • Animal Models for Studying Effects of Drugs of Abuse
    • Effects of CB1 Blockade on Effects of Drugs of Abuse
    • Neurobiological Pathways Affected by CB1 Blockade
    • Cannabinoid CB1 Receptor Blockade: A Step Forward in Drug-Dependence Therapy?
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