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Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys

Abstract

Rationale

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been suggested to play an important role in mediation of drug-reinforced behaviors, as well as in the mechanisms underlying relapse in abstinent subjects. The prototypical mGluR2/3 agonist, LY379268, has been shown to attenuate nicotine reinforcement and cue-induced reinstatement of drug seeking in rats, as well as reinstatement induced by drug-associated stimuli and contexts across different drugs of abuse (i.e., cocaine, heroin, and methamphetamine). However, in primates, LY379268 has been shown to produce conflicting results on abuse-related effects of cocaine, and there are no data available for nicotine.

Objectives

To explore the therapeutic potential of mGluR2/3 agonists, we compared the effects of LY379268 (0.03–1.0 mg/kg) on nicotine, cocaine, and food self-administration under a fixed-ratio (FR10) schedule in three separate groups of squirrel monkeys. Moreover, we studied the effects of LY379268 on nicotine/cocaine priming-induced and cue-induced reinstatement of drug-seeking behavior in nicotine- and cocaine-experienced groups of animals.

Results

LY379268 blocked nicotine, but not cocaine, self-administration in monkeys. There was a partial overlap between doses that affected nicotine and food self-administration. In abstinent monkeys, LY379268 dose-dependently blocked nicotine, but not cocaine, priming-induced reinstatement of drug seeking. In both cocaine-experienced and nicotine-experienced groups of animals, LY379268 potently reduced cue-induced reinstatement of drug-seeking behavior.

Conclusions

The present findings provide strong support for the potential utility of mGlu2/3 receptor agonists for the treatment of nicotine dependence and suggest their utility for prevention of relapse induced by environmental cues associated with drug taking.

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Acknowledgments

With great sadness, we dedicate this article to memory of Dr. Steven R. Goldberg (†November 25, 2014).

We thank Dr. Ira Baum and Philip White for their excellent veterinary assistance during the study. We thank Dr. Sevil Yasar for advice and administrative assistance with the study and Dr. Charles Schindler for his comments on the manuscript.

This work was supported in part by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, and in part by NIDA grant DA011946 to Dr. Markou.

Conflict of interest

Athina Markou holds a patent on the use of metabotropic glutamate receptors for the treatment of drug dependence. During the last 3 years, Athina Markou has received contract research support by Astra-Zeneca, Forest Laboratories, and Bristol-Myers Squibb and honoraria from AbbVie, Germany.

The other authors have no conflicts of interest to declare.

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Correspondence to Zuzana Justinova.

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Zuzana Justinova and Bernard Le Foll contributed equally to this work.

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Justinova, Z., Le Foll, B., Redhi, G.H. et al. Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys. Psychopharmacology 233, 1791–1800 (2016). https://doi.org/10.1007/s00213-015-3994-y

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  • DOI: https://doi.org/10.1007/s00213-015-3994-y

Keywords

  • Cocaine
  • Glutamate
  • Nicotine
  • Reinstatement
  • Relapse
  • Self-administration
  • Smoking cessation
  • Squirrel monkey