Role of the kappa opioid receptor system in learning and substance use disorders

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Project Summary Despite their high prevalence, the underlying neurobiology of substance use disorders is still not understood, limiting effective pharmacological treatment options. Characterized by disruptions in learning processes, substance use disorders are thought to develop with the transition from being motivated by the positive reinforcing effects of the substance, to negative reinforcement where use occurs to avoid or alleviate an aversive state during abstinence. It is hypothesized that substance-induced upregulations in kappa opioid receptor (KOR) signaling play a causal role in the dysphoria that drives negative reinforcement. In support of this idea, KOR antagonists decrease drug intake in models of chronic use or dependence and the nucleus accumbens, a region critical to reinforcement learning and motivated behaviors, is one of the regions in which substance use has been shown to upregulate the KOR system. Despite this evidence of a causal role for KOR signaling in substance use disorders, this system’s function in adaptive reinforcement processes and the sufficiency of its upregulation in driving maladaptive learning remains unknown. Here, we aim to address these issues through direct investigation of the role of the KOR system in positive and negative reinforcement learning through pharmacological manipulation, sub-second measurement of in vivo dynorphin dynamics, and optogenetic activation of the KOR system. In aim 1, I will pair systemic antagonism of the KOR system with positive and negative reinforcement operant conditioning tasks to elucidate the role of KOR signaling in adaptive learning. In aim 2, I will conduct sub-second resolution, in vivo optical imaging of dynorphin release in the nucleus accumbens to uncover the role of endogenous KOR system activity in encoding information during reinforcement learning processes. Finally, in aim 3, I will optogenetically evoke accumbal dynorphin release to determine the sufficiency of augmentation of the KOR system in driving the maladaptive learning that underlies addiction. Through the completion of this proposal, I will receive well-rounded training in conducting independent research and contribute to the field of addiction neuroscience’s understanding of the mechanism by which the KOR system is involved in adaptive and maladaptive reinforcement learning processes.