Midbrain D₃ Receptor Availability Predicts Escalation in Cocaine Self-administration

Background: Results from neuroimaging studies suggest that disruptions in flexible decision-making functions in substance-dependent individuals are a consequence of drug-induced neural adaptations. In addicted populations, however, the causal relationship between biobehavioral phenotypes of susceptibility and addiction consequence is difficult to dissociate. Indeed, evidence from animals suggests that poor decision making due to preexisting biological factors can independently enhance the risk for developing addiction-like behaviors. Neuroimaging studies in animals provide a unique translational approach for the identification of the neurobiological mechanisms that mediate susceptibility to addiction. Methods: We used positron emission tomography in rats to quantify regional dopamine D_2/3 receptors and metabotropic glutamate receptor 5 (mGluR5) and assessed decision making using a probabilistic reversal learning task. Susceptibility to self-administer cocaine was then quantified for 21 days followed by tests of motivation and relapse-like behaviors. Results: We found that deficits specifically in reward-guided choice behavior on the probabilistic reversal learning task predicted greater escalation of cocaine self-administration behavior and greater motivation for cocaine and, critically, were associated with higher midbrain D₃ receptor availability. Additionally, individual differences in midbrain D₃ receptor availability independently predicted the rate of escalation in cocaine-taking behaviors. No differences in mGluR5 availability, responses during tests of extinction, or cue-induced reinstatement were observed between the groups. Conclusions: These findings indicate that our identified D₃-mediated decision-making phenotype can be used as a behavioral biomarker for assessment of cocaine use susceptibility in human populations.