The Neural Regulation of Negative Affect in a New Model of Cocaine Seeking

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The development of negative emotional states as a result of chronic drug use has a profound impact on substance abuse disorder and has yet to be comprehensively modeled. This award will provide the basis for the refinement of such a model to be used in conjunction with state ofthe art neural electrochemical and electrophysiological measurement techniques to probe the influence of negative affect on drug seeking. The training from the first phase of this award provided the PI a unique skillset and understanding ofthe manner by which drugs of abuse alter and usurp the neural circuitry evolved to process the motivational and hedonic properties of natural rewards. Specific Aim 1 determined that rapid dopamine release in the nucleus accumbens (NAc) core and shell was differentially altered by rewarding and aversive taste stimuli as well as for a natural reward in situations in which it predicts cocaine versus when it does not. The results of this study have shown that a cocaine-predictive taste cue induces a negative affective state that is linked to increased early-session drug taking. This aversive state appears to be akin to a cue-induced withdrawal state and the results of Specific Aim 2 demonstrated that this negative affective state elevates intracranial self-stimulation (ICSS) reward thresholds, consistent with a conditioned withdrawal state. Specific Aim 3 will determine if distinct subregions ofthe NAc selectively process associative, versus hedonic aspects ofthe learned aversion to the cocaine-associated cue that promotes drug seeking. In Specific Aim 4, two experiments will probe the breadtl;) of this phenomenon and the control this negative affective state exerts on drug seeking. The results of these studies will demonstrate whether non-gustatory, drug-predictive cues also elicit a negative affective state that retards extinction responding and promotes relapse. Together these experiments will rigorously test the role of negative affect on drug seeking in rats and allow for a better general understanding of how the environment influences an animal's affect and subsequent behavior.