(-)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine (MTEP) similarly attenuate stress-induced reinstatement of cocaine seeking.

Metabotropic glutamate receptors (mGluRs) have been implicated in the regulation of anxiety, stress responses and the neurobehavioral effects of psychostimulants. The present study was designed to examine whether antagonizing mGluR5 or activating mGluR2/3 prevents stress-induced reinstatement of cocaine seeking. Male Wistar rats were trained to self-administer cocaine and then subjected to daily extinction training for 2 weeks. Subsequent exposure to 15 minutes of intermittent footshock elicited robust reinstatement of responding at the previously active lever. Both the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine (MTEP) (0-3 mg/kg, intraperitoneally) and the selective mGluR2/3 agonist (-)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) (0-3 mg/kg, subcutaneously) prevented cocaine seeking induced by footshock stress following the same dose-response function. The data show that although mGluR2/3 and mGluR5 are differentially located on synaptic compartments, both LY379268 and MTEP produced the same behavioral effects in reducing stress-induced reinstatement. These results are important because they demonstrate that a reduction in glutamate-mediated neural excitability (albeit via different mechanisms of action) reverses footshock-induced reinstatement and suggest that pharmacological manipulations of mGluR2/3 and mGluR5 can prevent the effects of stress, a major precipitating factor for relapse. These findings further confirm that mGluR2/3 or mGluR5 are promising targets for relapse prevention.