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Abstract

Though altered dopamine transmission is implicated in most contemporary theories of addiction, the timing, context, and directionality of these changes remain a matter of debate. While some studies demonstrate dopamine in the nucleus accumbens core (NAcc) plays an important role in producing drug satiety, others suggest NAcc dopamine mediates craving and promotes drug seeking.

How might drug-cue elicited dopamine transmission in the NAcc serve both as a satiety signal and to produce craving?  Drug cues serve different purposes in different contexts.  During drug-taking, cues confirm the success of drug-seeking actions and indicate imminent drug delivery, thus suppressing further drug-seeking. In contrast, during reinstatement paradigms, the same cues, presented unexpectedly during abstinence, signal possible drug availability nearby and promote drug-seeking.  For NAcc dopamine to both decrease drug-taking and increase drug-seeking, we hypothesize there must be a divergence in the dopamine signals evoked by drug-paired cues when presented in drug-taking vs. -seeking contexts.  To test this hypothesis we used fast-scan cyclic voltammetry in rats to measure changes in drug-cue elicited dopamine over time in both of these contexts.  Indeed, we found that while cue-elicited dopamine transmission significantly decreases over the course of weeks of drug-taking, dopamine responses to the same cues presented in a drug-seeking context increase.  We also found that the cue-elicited dopamine signals observed during drug-seeking ‘incubate’ further during prolonged periods of abstinence, and that this occurs in parallel with enhancements in drug-seeking behavior.  To confirm that changes in dopamine release were regulating the drug-taking and drug-seeking behavior we observed we also employed optogenetic manipulations of dopamine release to demonstrate that enhancing dopamine during drug-taking suppresses drug intake, and enhancing dopamine during drug-seeking promotes drug-seeking behaviors.