Dysregulation of Decision Making Related to Metabotropic Glutamate 5, but Not Midbrain D₃, Receptor Availability Following Cocaine Self-administration in Rats

Background: Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans. Methods: We assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the [¹¹C]-(+)-PHNO and [¹⁸F]FPEB radioligands to quantify regional dopamine D_2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. Results: We found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D_2/3 and, importantly, midbrain D₃ receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. Conclusions: These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals.