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 D2/3 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.
Bibliographical noteFunding Information:
This work was supported by the National Institute on Drug Abuse (Grant Nos. DA041480 and DA043443 [to JRT]), the National Institute on Alcohol Abuse and Alcoholism (Grant No. K01AA024788 [to ATH]), the Brain and Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression Young Investigator Award [to SMG]) and the State of Connecticut. SMG and JRT were responsible for conceptualization. SMG, KF, and DH were responsible for investigation. ATH and HL were responsible for software. SMG was responsible for analysis and writing the original draft. SMG, ATH, HL, KF, DH, EDM, DL, and JRT were responsible for writing, reviewing and editing. All authors approved the final version of the manuscript. We acknowledge the exceptional technical assistance provided by Cynthia Santaniello, Courtney Chabina, Amanda Harsche, Jessica Pursi, and Dayshalis Ofray. We also thank the Yale Positron Emission Tomography Center and Dr. Irina Esterlis for radioligand support as well as the Drug Supply Program at the National Institute on Drug Abuse for providing cocaine HCl. The authors report no biomedical financial interests or potential conflicts of interest.
This work was supported by the National Institute on Drug Abuse (Grant Nos. DA041480 and DA043443 [to JRT]), the National Institute on Alcohol Abuse and Alcoholism (Grant No. K01AA024788 [to ATH]), the Brain and Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression Young Investigator Award [to SMG]) and the State of Connecticut.
- Addiction susceptibility
- Cocaine self-administration
- Decision making
- Dopamine D receptor
- Metabotropic glutamate receptor 5
- Reinforcement learning