Alcohol/Stress Effects on Kappa Opioid Receptors in the Amygdala and Accumbens

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SUMMARY Stress is a well-known factor in promoting heavy drinking and relapse to drinking in individuals with alcohol use disorder (AUD), and avoidance of the negative affective symptoms of ethanol withdrawal (e.g. anxiety and depression) is also believed to play a critical role in relapse. Further, disorders of negative affect may predispose individuals to AUD and the interaction of these disorders may exacerbate symptoms of both. One component of the brain stress system is comprised of the neuropeptide dynorphin and its target, the kappa opioid receptors (KOR), and it is augmented following exposure to chronic alcohol and/or stress. We will use a mouse model of chronic intermittent ethanol (CIE) exposure combined with either chronic forced swim stress or mouse single prolonged stress to understand the role that KORs play in the maladaptive neurobiological changes induced by stress/ethanol interactions. Our previous work revealed that the function of the dynorphin/KOR system in the nucleus accumbens (NAc) was robustly up-regulated by chronic ethanol exposure and withdrawal in a time/exposure dependent manner in both the CIE model in mice and in a long- term voluntary ethanol drinking model in monkeys. In addition, in mice we found that systemic administration of a KOR antagonist reduced anxiety/compulsive behaviors (marble burying) and withdrawal-induced excessive drinking. Dopamine (DA) is involved in negative affective responses to stress, and DA terminals are known targets of KOR activity. Therefore, we will use a multipronged approach to examine KOR regulation of DA signaling in the NAc, which regulates motivation to drink alcohol, and the basolateral amygdala (BLA), which regulates stress/anxiety-related behaviors, using conditional viral knockdown of KORs from these regions, microdialysis to assess basal dopamine and dynorphin levels following exposure to CIE and/or stress paradigms, and the fluorescent sensor dLight to query real-time dopamine signaling in these animals in response to time-locked behaviors. The overall goal of this proposal is to define the role of KORs on DA signaling in the NAc and BLA following exposure to chronic alcohol and/or stress, and how these adaptations in stress-responsive limbic circuitry nodes that are responsible for withdrawal-associated negative affect can be targeted for the treatment of AUD.