Oprk1-regulated neurocircuitry and phenotypes of alcohol use disorder

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Project Summary. A fundamental characteristic of alcohol use disorders is the loss of control over alcohol consumption that results in progressively escalating levels of alcohol use and facilitates the progression to alcohol-dependence. Given the comorbidity of alcohol dependence and disorders of affect such as depression is extremely high, it has been posited that self-medication of negative affective states contributes to continued excessive alcohol use and relapse. Furthermore, negative affective states produced by chronic alcohol exposure can influence the neurocircuitry of cognitive control systems to perpetuate further excessive alcohol use. Once that degree of dysregulation is reached, components of the dependence cycle serve to facilitate each other in a manner that is extremely deleterious to personal, familial and societal welfare. The principal investigator’s long-term goal is to identify effective therapeutic targets and strategies for the treatment of alcohol use disorder (AUD). The objective of this application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in Oprk1 (kappa-opioid receptor gene)-regulated systems that occur in response to chronic alcohol exposure and contribute to maladaptive behavioral regulation. The central hypothesis is that the Oprk1-regulated neurocircuitry becomes progressively dysregulated in a manner that promotes the continued excessive consumption of alcohol and perpetuates the cycle of alcohol dependence. The rationale for the proposed studies is that understanding the contribution of dysregulated Oprk1 expression in AUD will lay the foundation for the development of effective therapies designed to alleviate maladaptive behavioral regulation produced by alcohol dependence. This hypothesis will be tested by utilizing inducible and conditional CRISPR/CAS9 gene editing and chemogenetic approaches to recapitulate or ameliorate symptoms of alcohol dependence in non-selected and transgenic rats. Animal models of operant alcohol self-administration, negative affective-like behavior and executive function including working memory will serve as functional end-points to systematically investigate the role of Oprk1 expression in maladaptive behavioral regulation related to alcohol dependence. In addition, Oprk1 gene expression will be assessed as a complement to the behavioral approaches. The proposed research will help to identify the functional importance of neuroadaptations in Oprk1-regulated systems that result from chronic alcohol exposure and will provide much needed information regarding the influence of Oprk1 on the neurocircuitry of AUD-related phenotypes. Such a contribution is significant because it will help identify and develop therapeutic targets to treat AUD that focus on the removal of maladaptive phenotypes; a strategy that should greatly increase treatment compliance and decrease rates of relapse.