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Attenuation of cue-induced reinstatement of nicotine seeking by URB597 through cannabinoid CB1 receptor in rats

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Abstract

Rationale

The endocannabinoid system is composed of endocannabinoids (such as anandamide), their target receptors (CB1 and CB2 receptors, CB1Rs and CB2Rs), the enzymes that degrade them (fatty-acid-amide-hydrolase (FAAH) for anandamide), and an endocannabinoid transporter. FAAH inhibition has been recently identified as having a critical involvement in behaviors related to nicotine addiction and has been shown to reduce the effect of nicotine on the mesolimbic dopaminergic system via CB1R and peroxisome proliferator-activated receptor alpha (PPARα). Thus, inhibition of FAAH may represent a novel strategy for smoking cessation, but its mechanism of action on relapse to nicotine seeking is still unknown.

Objective

The study aims to explore the mechanism of action of the inhibitor of FAAH activity, URB597, on relapse to nicotine seeking by evaluating the effect of the CB1R, CB2R, and PPARα antagonists on the attenuating effect of URB597 on cue-induced reinstatement of nicotine seeking in rats.

Results

URB597 reduced cue-induced reinstatement of nicotine seeking, an effect that was reversed by the CB1R antagonist rimonabant, but not by the CB2R or PPARα antagonists AM630 and MK886, respectively.

Conclusions

These results indicate that URB597 reduces cue-induced reinstatement in rats through a CB1 receptor-dependent mechanism, and not via CB2R or PPARα. Since FAAH inhibition represent a novel and promising strategy for tobacco smoking cessation, dissecting how it produces its action may lead to a better understanding of the neurobiological mechanisms underlying nicotine addiction.

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Acknowledgments

We thank A. Pushparaj for his help during the experiments and comments on the manuscript. The experiments comply with the current laws of Canada.

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Authors and Affiliations

  1. Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, CAMH, 33 Russell Street, Toronto, ON, Canada, M5S 2S1

    Benoit Forget, Mihail Guranda, Islam Gamaleddin & Bernard Le Foll

  2. Institut Pasteur, Unité de Neurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, 75724, Paris Cedex 15, France

    Benoit Forget

  3. Institute of Environmental Studies and Research, Ain Shams University, Cairo, Egypt

    Islam Gamaleddin

  4. Preclinical Pharmacology Section, Behavioral Neurosciences Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, MD, USA

    Steven R. Goldberg

  5. Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, CAMH, Toronto, ON, Canada

    Bernard Le Foll

  6. Departments of Family and Community Medicine, Pharmacology, Psychiatry, Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada

    Bernard Le Foll

Authors
  1. Benoit Forget
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  2. Mihail Guranda
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  3. Islam Gamaleddin
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  4. Steven R. Goldberg
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  5. Bernard Le Foll
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Corresponding author

Correspondence to Bernard Le Foll.

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Funding

This work was supported by a grant from the Heart and Stroke Foundation no. NA 6901.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

In memoriam of Steven R. Goldberg

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Forget, B., Guranda, M., Gamaleddin, I. et al. Attenuation of cue-induced reinstatement of nicotine seeking by URB597 through cannabinoid CB1 receptor in rats. Psychopharmacology 233, 1823–1828 (2016). https://doi.org/10.1007/s00213-016-4232-y

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  • DOI: https://doi.org/10.1007/s00213-016-4232-y

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