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Inhibition of fatty acid amide hydrolase reduces reinstatement of nicotine seeking but not break point for nicotine self-administration—comparison with CB1 receptor blockade

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Abstract

Rationale

The endocannabinoid system has been recently identified as having critical involvement in drug taking and relapse phenomenon for various drugs of abuse and notably nicotine. The endocannabinoid system consists of endocannabinoids (such as anandamide), their target receptors (mostly cannabinoid CB1 receptors), and the enzymes that degrade those endocannabinoids (fatty-acid-amide-hydrolase (FAAH) for anandamide). It has been recently identified that the utility of rimonabant for smoking cessation may be limited by its psychiatric side effects. Therefore, there is a great need to develop alternative ways of modulating the cannabinoid system that will be better tolerated.

Objective

The aim of the study was to explore the effect of inhibiting FAAH enzyme by URB597 on nicotine self-administration under a progressive ratio schedule and reinstatement of nicotine seeking, in comparison with the effect of the CB1 antagonist rimonabant.

Results

Rimonabant, but not URB597, dose-dependently reduced the break point for nicotine self-administration, an effect that was stable over repeated administrations. Rimonabant and URB597 significantly decreased the reinstatement of nicotine seeking induced either by presentation of nicotine-associated stimuli or by nicotine priming.

Conclusions

These results indicate that the integrity of the CB1 receptors is necessary for the incentive motivation of the rats for nicotine and that FAAH inhibition may be as effective as CB1 receptor blockade to prevent reinstatement of nicotine seeking. Since FAAH inhibition present antidepressant and anxiolytic properties in rodents, targeting the FAAH may represent a novel strategy to prevent relapse for tobacco smoking that may be better tolerated than rimonabant.

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Acknowledgments

BF was funded by a CIHR Strategic Training Program in Tobacco Research Fellowship and BLF was funded by a New Investigator Fellowship from the Tobacco Use in Special Population Training Program from the Canadian Institutes of Health Research (CIHR).

Disclosure/conflicts of interest

The authors do not have any conflicts of interest, financial or otherwise, that might bias this work.

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Authors and Affiliations

  1. Translational Addiction Research Laboratory, Centre for Addiction and Mental Health (CAMH), 33 Russell Street, Toronto, Canada, M5S 2S1

    Benoit Forget, Kathleen M. Coen & Bernard Le Foll

  2. Department of Family and Community Medicine, University of Toronto, Toronto, Canada

    Bernard Le Foll

  3. Department of Pharmacology, University of Toronto, Toronto, Canada

    Bernard Le Foll

  4. Department of Psychiatry, University of Toronto, Toronto, Canada

    Bernard Le Foll

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  1. Benoit Forget
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  2. Kathleen M. Coen
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  3. Bernard Le Foll
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Correspondence to Bernard Le Foll.

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Forget, B., Coen, K.M. & Le Foll, B. Inhibition of fatty acid amide hydrolase reduces reinstatement of nicotine seeking but not break point for nicotine self-administration—comparison with CB1 receptor blockade. Psychopharmacology 205, 613–624 (2009). https://doi.org/10.1007/s00213-009-1569-5

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  • DOI: https://doi.org/10.1007/s00213-009-1569-5

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