Cocaine Potency at the Dopamine Transporter Tracks Discrete Motivational States During Cocaine Self-Administration.

Abstract

Although the dopamine transporter (DAT) is the primary site of action for cocaine, and the dopamine system is known to mediate the reinforcing effects of cocaine, the dopaminergic variations underlying individual differences in cocaine self-administration behaviors are not fully understood. Recent advances in the application of economic principles to operant tasks in rodents have allowed for the within-subject, within-session determination of both consummatory and appetitive responding for reinforcers. Here we combined a behavioral economics approach with cocaine self-administration and ex vivo voltammetric recording of dopamine signaling in the core of the nucleus accumbens of rats to determine the relationship between dopamine signaling and discrete aspects of cocaine taking and seeking. We found neither dopamine release or uptake tracked individual differences in cocaine consumption or the reinforcing efficacy of cocaine. Cocaine potency at the DAT was correlated with reinforcing efficacy, but was not related to cocaine consumption. Further, we introduce a novel analysis that determines perseverative responding within the same procedure, and find that cocaine potency at the DAT also tracks differences in perseverative responding. Together, we demonstrate that cocaine effects at the DAT determine the reinforcing efficacy of cocaine, and perseverative responding for sub-threshold doses of cocaine that do not maintain responding when presented in isolation. Surprisingly, we find that variations in cocaine potency do not account for differences in cocaine consumption, suggesting that satiation for cocaine is determined by other targets or mechanisms. Finally, we outline a novel approach for relating drug-target interactions and potency to discrete motivational states during a single self-administration session.