Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats

Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2 mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased. mGluR2 mutant rats also show a lower propensity to relapse after a period of cocaine abstinence, an effect associated with reduced cocaine-induced dopamine and glutamate overflow in the nucleus accumbens. These findings suggest that mGluR2 polymorphisms or reduced availability of mGluR2 might be risk factors for the initial development of cocaine use but could actually protect against addiction by reducing sensitivity to cocaine reward. [Display omitted] •mGluR2 deletion reduces sensitivity to cocaine reward•mGluR2 deletion causes an increase in cocaine self-administration and in cocaine intake•mGluR2 deletion causes a reduction in relapse to drug-seeking behavior•mGluR2 deletion causes a reduction in dopamine and glutamate responses to cocaine The etiology and pathophysiology of drug addiction remain poorly understood. Yang et al. show that genetic deletion of mGluR2, a presynaptic glutamate autoreceptor, decreases sensitivity to cocaine reward that causes a compensatory increase in cocaine taking and a decrease in relapse to cocaine-seeking behavior in rats.