Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory.

Background: The perseverance of the motivational salience of drug-associated memories is an obstacle to the successful treatment of drug addiction and is often a causative factor in triggering relapse.

Methods: This study was intended to determine whether potentiation of type 5 metabotropic glutamate receptors (mGluR5), which are biochemically and structurally coupled to N-methyl-D-aspartate (NMDA) receptors, would facilitate the extinction of a cocaine-associated contextual memory as assessed by the conditioned place preference (CPP) paradigm in rats. Following the establishment of a cocaine CPP, rats were treated with the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; 0.3, 3 and 30 mg/kg) before extinction test sessions. Additional groups of animals received 30 mg/kg CDPPB in combination with the mGluR5 antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP, 1 mg/kg) or the NMDA receptor antagonist MK-801 (.1 mg/kg).

Results: CDPPB dose-dependently facilitated the extinction of cocaine CPP, and these effects were not observed when animals were coadministered MTEP or MK-801. CDPPB failed to produce any evidence of neurotoxicity as assessed by FluoroJade C staining.

Conclusions: Positive allosteric modulation of mGluR5 function facilitates the extinction of a cocaine-associated contextual memory, which may represent a novel approach toward enhancing extinction learning in the context of drug addiction.