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.

• Authors: Zuzana Justinova, Bernard Le Foll, Godfrey H Redhi, Athina Markou, Steven R Goldberg
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 233 Issue 10 Pg. 1791-800 (05 2016) ISSN: 1432-2072 [Electronic] Germany
• PMID: 26149611 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Amino Acids
• Bridged Bicyclo Compounds, Heterocyclic
• LY 379268
• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor 2
• metabotropic glutamate receptor 3
• Nicotine
• Cocaine

Topics

• Amino Acids (pharmacology)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cocaine (administration & dosage)
• Cocaine-Related Disorders (drug therapy)
• Cues
• Dose-Response Relationship, Drug
• Drug Interactions
• Drug-Seeking Behavior (drug effects)
• Male
• Nicotine (administration & dosage)
• Receptors, Metabotropic Glutamate (agonists)
• Recurrence
• Reinforcement, Psychology
• Saimiri
• Self Administration
• Tobacco Use Disorder (drug therapy)