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Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal

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Abstract

Rationale

The involvement of metabotropic glutamate 5 (mGlu5) receptors has been suggested in the reinforcing effects of psychostimulants. However, little is known about the role of these receptors in psychostimulant withdrawal.

Objectives

The role of mGlu5 receptors was assessed in the anhedonic and somatic aspects of psychostimulant withdrawal.

Methods

Anhedonia was assessed with the discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure after the termination of cocaine (180 mg kg−1 day−1, salt, 3 days, i.p.) or nicotine (40 mg kg−1 day−1, base, 28 days, s.c.) administration via osmotic minipumps in mGlu5 receptor knockout (mGluR5−/−) and wild-type (mGluR5+/+) mice. Somatic signs were assessed during nicotine withdrawal. The effects of the nicotinic acetylcholine receptor antagonist mecamylamine on ICSS thresholds were assessed during chronic nicotine administration.

Results

Nicotine-treated mGluR5+/+ and mGluR5−/− mice demonstrated similar threshold elevations during mecamylamine-precipitated withdrawal compared with their saline-treated counterparts. During spontaneous nicotine and cocaine withdrawal, thresholds in drug-withdrawing mGluR5+/+, but not mGluR5−/−, mice were elevated up to 72 h of nicotine/cocaine withdrawal and then returned to baseline, indicating attenuation of withdrawal-induced anhedonia in mGluR5−/− mice. Nicotine-withdrawing mGluR5+/+, but not mGluR5−/−, mice showed increases in somatic signs compared with saline-treated counterparts.

Conclusions

mGlu5 receptor null mutation attenuates the anhedonic and somatic effects of psychostimulant withdrawal. This attenuated withdrawal in mGluR5−/− mice may result from the lack of drug-induced adaptations in mGlu5 receptor function that may occur in mGluR5+/+ mice with chronic drug administration. Thus, these results suggest the involvement of mGlu5 receptors in psychostimulant dependence and the mediation of the anhedonic and somatic signs of psychostimulant withdrawal.

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Acknowledgements

This work was supported by NIH grant R01DA023209 to AM. The authors thank Novartis for providing the mGlu5 knockout breeding pairs, Mr. Edwin Obaña and Mrs. Kimberly Edwards for their assistance with mouse colony maintenance and genotyping of the mGlu5 receptor knockout line, Dr. Manoranjan D’Souza for input during the preparation of this manuscript, and Mr. Michael Arends for editorial assistance.

Conflicts of interest

AM has received contract research support from Intracellular Therapeutics, Inc., Bristol-Myers-Squibb Co., F. Hoffman-La Roche Inc., Pfizer, and Astra-Zeneca and honorarium/consulting fees from Abbott GmbH and Company, AstraZeneca, and Pfizer during the past 3 years. AM has a patent application on metabotropic glutamate receptors and drug dependence. AKS and BO have no disclosures and no conflicts of interest.

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  1. Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA

    Astrid K. Stoker & Athina Markou

  2. Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg, 3584 CG, Utrecht, The Netherlands

    Astrid K. Stoker & Berend Olivier

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  1. Astrid K. Stoker
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  2. Berend Olivier
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Correspondence to Athina Markou.

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Stoker, A.K., Olivier, B. & Markou, A. Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal. Psychopharmacology 221, 317–327 (2012). https://doi.org/10.1007/s00213-011-2578-8

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