Received for publication March 28, 2006.
Revised May 3, 2006.
Accepted for publication May 3, 2006.

Pharmacological Stimulation of Group II Metabotropic Glutamate Receptors Reduces Cocaine Self-Administration and Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys

Abstract

Group II metabotropic glutamate receptors (mGluRs) have been implicated in regulating the psychopharmacologic effects of cocaine and other drugs of abuse. The present study investigated the interactions between the Group II mGluR agonist (-)-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate (LY379268) and cocaine in squirrel monkeys whose behavior was: 1) maintained under a second-order schedule of i.v. drug self-administration in which lever pressing was reinforced by injections of cocaine either with or without presentations of a cocaine-paired visual stimulus, 2) extinguished and then reinstated by priming injections of cocaine with or without presentations of the cocaine-paired stimulus, and 3) controlled by cocaine trained as a discriminative stimulus. Antagonism studies with the Group II mGluR antagonist 2S-2-amino-2-(1S, 2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl) propanoic acid (LY341495) investigated the extent to which the cocaine-modulating effects of LY379268 could be reversed by blocking Group II mGluRs. Quantitative observational studies investigated the effects of LY379268 and LY341495 on species-typical behaviors, balance and muscle resistance. Pretreatment with LY379268 reduced cocaine self-administration and cocaine-induced reinstatement of drug seeking in a dose-dependent, LY341495-reversible manner. Significant effects of LY379268 were observed both in the presence and absence of the cocaine-paired stimulus. LY379268 did not alter the discriminative stimulus effects of cocaine; nor did it markedly affect observed behavior, with the exception of an increase in visual scanning. Emesis frequently was observed after the highest dose of LY379268 (1.0 mg/kg). The results suggest that LY379268, by stimulating Group II mGluRs, attenuates the reinforcing and priming effects of cocaine without altering its perceptibility or suppressing other behaviors.

Key words: cocaine, drug discrimination, drug self-administration, mGluR agonist, mGluR antagonist, reinstatement of drug seeking

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