The metabotropic glutamate 5 receptor is necessary for extinction of cocaine-associated cues

Background and PurposeThere is currently no medication approved specifically to treat cocaine addiction. Behavioural interventions such as cue exposure therapy (CET) rely heavily on new learning. Antagonism of the metabotropic glutamate 5 (mGlu(5)) receptor has emerged as a potential treatment, by reducing the reinforcing properties of cocaine. However, mGlu(5) receptor activity is necessary for learning; therefore, such agents could interfere with behavioural treatments. We used a novel rodent model of CET to test the effects of mGlu(5) negative and positive allosteric modulators (NAM and PAM) on behavioural therapy. Experimental ApproachRats were trained to press a lever for cocaine in the presence of a discrete cue [conditioned stimulus (CS)] and then extinguished in the absence of the CS. Following lever extinction, half the rats received CS extinction in the same chambers but with the levers withdrawn; the remaining rats received no CS extinction. Before this session, rats received a systemic administration of either vehicle or a mGlu(5) NAM (MTEP, experiment 1) or PAM (CDPPB, experiment 2). Cue-induced reinstatement was tested in a drug-free session the following day. Key ResultsAt reinstatement, rats that had received CS extinction showed reduced responding. This effect was attenuated by MTEP treatment before CS extinction. In contrast, administration of CDPPB (PAM) led to decreased reinstatement the following day, regardless of extinction condition. Conclusion and ImplicationsThese results suggest that mGlu(5) receptor activity is both necessary and sufficient for efficient extinction of a cocaine-associated CS. Therefore, mGlu(5) PAMs could enhance the efficacy of CET.