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

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DESCRIPTION (provided by applicant): 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 of the art neural electrochemical and electrophysiological measurement techniques to probe the influence of negative affect on drug seeking. This training will provide the PI a unique skill set and understanding of the 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 will determine if rapid dopamine release in the nucleus accumbens (NAc) core and shell is similarly altered by rewarding and aversive taste stimuli as well a for a natural reward in situations in which it predicts cocaine versus when it does not. The results will broaden our understanding of the role of dopamine in associative learning and hedonic processing. We 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 may be akin to a cue-induced withdrawal state. Specific Aim 2 will test this hypothesis by examining the influence of the negative affective state on responding for intracranial self-stimulation (ICSS). The results of this study will demonstrate whether ICSS thresholds are elevated after the presentation of the cocaine predictive taste, consistent with a cue-induced withdrawal state. Specific Aim 3 will determine if distinct subregions of the NAc selectively process associative, versus hedonic aspects of the learned aversion to the cocaine-associated cue that promotes drug seeking. In Specific Aim 4, two experiments will probe the breadth 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 while providing training in electrochemical and behavioral techniques under the guidance of experts in their respective fields. PUBLIC HEALTH REVELANCE: The findings of these studies will shape our view and treatment of substance abuse disorders. A negative emotional state is associated with drug seeking and relapse in human addicts. The PI will investigate the motivational properties and neural underpinnings of this state that promotes drug seeking. Such investigations could lead to new pharmacotherapies aimed at disrupting the motivation to seek cocaine.