Optogenetic manipulation of dopamine signaling, negative affect and drug seeking

Marquette University, Milwaukee WI

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Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Aversive environmental events (e.g. loss of employment, fight with spouse, etc.) influence the daily lives of all people by altering their emotional states, decision making, and motivated behavior. For individuals with substance abuse disorders who are attempting to remain abstinent, these unfortunate events are clinically relevent, as they are frequently cited as a principle cause of relapse. In order to develop strategies to protect against this important determinant of relapse, it is essential to thoroughly characterize mechanisms by which aversive stimuli influence affective and motivational neural circuitry. To that end, several decades of research have identified the nucleus accumbens as a critical limbic motor interface, heavily regulated by dopamine, where affective and associative reward information directly influence behavioral output. Unfortunately, the manner by which aversive stimuli regulate dopamine signaling remains poorly understood, with several studies producing conflicting results. These discrepant results reflect both parametric experimental constraints and the inability of traditional measures to resolve the role of dopamine with sufficient spatial and temporal precision. This proposal details several experiments that will combine optogentic, electrophysiological, and electrochemical approaches in behaving animals that have a history of cocaine self-administration to clarify the causal relationship between negative affect-inducing aversive environmental events, decreased dopamine signaling, and drug seeking. Simultaneously, these experiments will directly test the sufficiency of decreased dopamine signaling in modulating nucleus accumbens' electrophysiological activity, hedonic responses, and drug seeking. The studies will determine if site-specific modulation of these discrete circuits reverses negative affective responses and prevents drug seeking. Specific Aim 1 will determine the causal role of aversive stimuli in promoting cocaine-seeking and simultanously characterize the precise role of dopamine signaling in each stage of the process: from the experience of the aversive stimulus to the transition to the cocaine-seeking state. Specific Aim 2 will determine if the decreased dopamine signaling observed following the presentation of cocaine-predictive stimuli is sufficient to cause drug seeking, and if this effect can be blocked by regulating dopamine. Specific Aim 3 will determine the discrete influence of dopamine on the encoding of reward and aversion-related behaviors by nucleus accumbens neurons. Together, the results of the proposed studies will provide unprecedented insight into the mechanism by which aversive stimuli alter the affective state of the animal, dopamine signaling, and drug seeking. The goal is to identify an aversion-sensitive motivational pathway that can be manipulated to protect abstinent substance abusers from a principle cause of relapse.