Abstract

<b>Abstract ID 13647</b> <b>Poster Board 413</b> The mesolimbic dopamine system, which plays an important role in motivated promotes[MRM1] rewarding[MRM2] behavior, is modulated by drugs of abuse. Drugs can alter cellular activity and gene expression within the ventral tegmental area (VTA), promoting behaviors associated with addiction. Previous work in our lab found that chronic cocaine and morphine administration increased both the activity and phosphorylation (at Ser78) of serum- and glucocorticoid-inducible kinase 1 (SGK1) in the VTA.[MRM3] Using a viral vector strategy to overexpress a catalytically inactive SGK1 mutant (K127Q), we have found that decreasing SGK1 activity in VTA dopamine neurons is sufficient to reduce cocaine conditioned place preference (CPP), supporting that our biochemical changes are functionally relevant. However, it is unclear whether SGK1 phosphorylation also alters drug-elicited behavior. Here, we present data that decreasing VTA SGK1 phosphorylation is also sufficient to reduce drug responses. We utilized viral vectors to overexpress SGK1 mutants that either prevent (S78A) or mimic (S78D) SGK1 Ser78 phosphorylation in the VTA. We found that preventing SGK1 phosphorylation (via S78A) decreased cocaine CPP and morphine preference in a two-bottle choice assay, while mimicking S78 phosphorylation (via S78D) did not alter either behavior (n = 14-21 mice/group for CPP with p &lt; 0.001, n = 16-18 mice/group for morphine preference with p &lt; 0.05). Together, these data support that decreasing either VTA SGK1 catalytic activity or phosphorylation is sufficient to reduce drug-elicited behavior. Thus, we hypothesized that SGK1 pharmacological inhibition may be a translational approach to decrease drug behavior. Using Neuro2A cells, we validated that the SGK1 inhibitor GSK650349 dose-dependently decreased phosphorylation of the exclusive SGK1 substrate, NDRG. Interestingly, we also observed that GSK650349 decreased SGK1 S78 phosphorylation, suggesting pharmacological inhibition may decrease both SGK1 catalytic activity and phosphorylation. To assess whether GSK650349 could prevent drug-induced changes in VTA SGK1 activity and phosphorylation, we pretreated mice for 7 days with GSK650349 (5mg/kg, i.p.) or vehicle, then administered GSK650349 for 7 days with morphine (20mg/kg) or saline. Via western blot, we found that morphine treatment significantly increased VTA SGK1 catalytic activity and S78 phosphorylation in vehicle-treated mice as expected, while morphine mice treated with GSK650349 did not differ from saline controls (n = 11-15 mice/group). These data support that systemic GSK650349 administration is sufficient to alter SGK1 activity within the brain. We are now determining whether systemic GSK650349 can reduce drug-elicited behavior. I will investigate the effects of GSK650349 administration on cocaine locomotor sensitization, cocaine CPP, and morphine preference using a two-bottle choice test. Our preliminary data suggest that GSK650349 (5mg/kg) is sufficient to blunt cocaine-induced locomotor activity, but not cocaine CPP. Together, our data support a role for SGK1 activity and phosphorylation in drug responses and suggest that SGK1 inhibition could provide a novel avenue for therapeutic intervention.

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