Determination of the role of ventral tegmental area SGK1 catalytic activity and phosphorylation in drug behavior

Substance use disorder is a chronic, relapsing disease that affects 20.3 million people in the United States. Despite its prevalence, treatments remain inadequate in part due to our limited understanding of the neuroadaptations induced by drug use. Drugs of abuse are known to regulate the activity of the mesolimbic dopamine (DA) system, a key circuit for drug action and reward. Specifically, drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation have been linked to behavioral outputs associated with addiction. Previous work determined that serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression, catalytic activity, and phosphorylation were increased by chronic administration of cocaine or morphine; however, it was unknown if these changes contributed to drug reward behaviors. In this thesis, I utilized transgenic and viral-mediated SGK1 manipulations to determine the impact of altered SGK1 expression and function on cocaine and morphine related-behaviors, primarily assessed by cocaine conditioned place preference (CPP) and voluntary morphine intake using a two-bottle choice task. I first established that that while SGK1 is transcriptionally upregulated and biochemically modified by chronic-drug administration, SGK1 deletion in either the VTA or in DA neurons was not capable of altering drug reward behaviors. Though SGK1 gene deletion did not alter reward, I next showed that viral-mediated overexpression of SGK1 mutants in the VTA of adult mice produced behaviorally relevant effects on cocaine and morphine reward. Specifically, intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine CPP and morphine preference, suggesting that decreased VTA SGK1 activity is sufficient to impair drug reward. To more fully understand the role of VTA SGK1 in behaviors relevant to addiction, I manipulated SGK1 expression in a cell type-specific manner to determine whether SGK1 activity in VTA DA or GABA neurons drove the observed behavioral effects. Utilizing novel Cre-dependent viral constructs, I found that reduced SGK1 activity in VTA DA neurons significantly decreases cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. Interestingly, this manipulation did not alter morphine preference. Future studies seek to determine a potential mechanism for these behavioral effects using ex vivo slice electrophysiology, and parallel studies currently explore the potential effects of a similarly regulated SGK1 phosphorylation site (Ser78) in drug-related behaviors. Altogether, these studies will allow for the identification of the specific cells and circuits that are critical for SGK1-mediated effects on drug reward and intake, a necessary step in assessing the feasibility of SGK1 inhibition as a novel therapeutic avenue for addiction.