Individual Differences & Cocaine Effects on Impulsive Choice in Rat

Cocaine dependence is associated with dysfunctional midbrain cortico-limbic-striatal circuits that impact decision-making processes and lead to the development of compulsive drug-seeking behaviors. Our new and published data from the prior funding period show that (1) that the reinforcement-learning mechanisms that predict cocaine-taking behaviors (e.g., positive-outcome updating) differ from those that are disrupted following cocaine self-administration (e.g., negative-outcome updating), (2) that midbrain D3 BPND is predictive of cocaine-taking behaviors and related to positive-outcome updating, but cocaine self-administration disrupts prefrontal cortical (PFC) mGlu5 BPND and is related to negative-outcome updating, and (3) that positive- outcome updating is controlled by amygdala projections to the PFC whereas negative-outcome updating is controlled by PFC projections to the nucleus accumbens (NAc). These findings, collectively, indicate that the biobehavioral mechanisms that mediate vulnerability to cocaine-taking behaviors differ from those that are disrupted by chronic cocaine exposure and identify midbrain D3 and cortical mGlu5 receptors as critical mediators of susceptibility to and consequence of cocaine use, respectively. The functional relevance of midbrain dopamine D3 and cortical mGlu5 BPND on the neural activity associated with addiction-relevant behaviors, however, is not known. The studies proposed here will investigate the role of D3 and mGlu5 BPND in circuit-level mechanisms of decision-making and drug-seeking behaviors in rats. We will use positron emission tomography (PET) and calcium imaging with fiber photometry to determine how D3 and mGlu5 BPND are associated with circuit-level activity in rats before and after cocaine self-administration. In Aim 1 we will investigate the relationship between individual differences in midbrain dopamine D3 BPND and dynamic neural activity in cortico-limbic circuits during decision making and subsequent cocaine self-administration behaviors. In Aim 2 we will determine how disruptions in mGlu5 glutamatergic signaling and neural activity mediate addiction-relevant (seeking/taking) behaviors and alter decision-making strategies after short and long periods of abstinence from cocaine self-administration. Together, our integrative and novel approach – combining sophisticated behavioral tasks, computational analyses, in vivo recordings of neural activity with calcium fiber photometry, and PET imaging – will determine the functional impact and neurobiological mechanisms of decision-making circuits and their role in addiction vulnerability and pathology.