Metabotropic glutamate 5 modulators: potential agents for treating cocaine addiction

There is ongoing interest in the role of the metabotropic glutamate 5 (mGlu5) receptor in cocaine-seeking behavior. Here we review the evidence from preclinical models that mGlu5 modulators might have a place in the treatment of cocaine addiction. mGlu5-negative allosteric modulators attenuate the incentive value of cocaine, and hence typically decrease cocaine self-administration and relapse to cocaine-seeking after extinction. However, it also seems that mGlu5 receptor distribution alters following extended cocaine exposure followed by withdrawal. Furthermore, in key circuits there is a switch from mGlu5-dependent to mGlu1-dependent transmission with increasing cocaine experience. Therefore, an mGlu5-negative allosteric modulator may be less effective in treating long-term cocaine addiction. On the other hand, mGlu5-positive allosteric modulators have cognitive enhancing effects, and mGlu5 is necessary for the inhibitory learning (extinction) that forms the basis of many behavioral treatments for addiction. Therefore, we propose that mGlu5-positive allosteric modulators, in conjunction with behavioral therapy, may prove a worthwhile strategy for treating cocaine addiction.