The mechanisms by which drugs of abuse, such as morphine and cocaine, induce long-term neuroadaptations that underlie addiction have not yet been fully defined. One promising brain region for study is the dopamine-rich ventral tegmental area (VTA), known to play a critical role in reward. Given recent evidence that chronic drug exposure increases VTA expression of serum- and glucocorticoid-inducible kinase 1 (SGK1), we wanted to investigate whether chronic drug exposure also increases SGK1 kinase activity and if altering VTA SGK1 activity affects drug reward behaviors. We found that chronic, but not acute, morphine or cocaine administration increased phosphorylation of SGK1 at S78 as well as phosphorylation of an SGK1 substrate, NDRG. To then investigate whether VTA SGK1 activity influences drug reward behaviors, we generated herpes simplex virus (HSV) constructs for local, short-term overexpression of SGK1 mutants. We found VTA expression of catalytically inactive SGK1-K127Q significantly lowered voluntary morphine consumption compared to constitutively active SGK1-S422D. We next examined cocaine locomotor activity and conditioned place preference (CPP) behaviors. Both HSV-GFP and HSV-K127Q mice exhibited locomotor sensitization to cocaine and robust CPP; however, there were no significant differences between the two groups. Given the complexity in these results, future studies will be needed to more fully understand the role of VTA SGK1 activity in reward behavior, including the specific role of S78 phosphorylation. We hope that such studies may identify molecular mechanisms underlying drug dependence that might serve as novel targets for therapeutic intervention in addiction.
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