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Background  We previously identified a group of glucocorticoid-responsive genes, including Serum Glucocorticoid kinase 1 (Sgk1), regulated by acute ethanol in prefrontal cortex of DBA2/J mice. Acute ethanol activates the hypothalamic pituitary adrenal axis (HPA) causing release of glucocorticoids. Chronic ethanol dysregulates the HPA response in both humans and rodents, possibly contributing to important interactions between stress and alcoholism. Because  Sgk1  regulates ion channels and learning and memory, we hypothesized that  Sgk1  contributes to HPA-dependent acute and adaptive neuronal responses to ethanol. These studies characterized acute and chronic ethanol regulation of  Sgk1  mRNA and protein and their relationship with ethanol actions on the HPA axis.    Results  Acute ethanol increased  Sgk1  mRNA expression in a dose and time dependent manner. Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the  Sgk1  promoter; adrenalectomy blocked ethanol induction of  Sgk1  mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and  Sgk1  induction by acute ethanol. SGK1 protein had complex temporal responses to acute ethanol with rapid and transient increases in Ser422 phosphorylation at 15 min. following ethanol administration. This activating phosphorylation had functional consequences, as suggested by increased phosphorylation of the known SGK1 target, N-myc downstream-regulated gene 1 (NDRG1). After repeated ethanol administration during locomotor sensitization, basal SGK1 protein phosphorylation increased despite blunting of  Sgk1  mRNA induction by ethanol.    Conclusions  These results suggest that HPA axis and glucocorticoid receptor signaling mediate acute ethanol induction of  Sgk1  transcription in mouse prefrontal cortex. However, acute ethanol also causes complex changes in SGK1 protein expression and activity. Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of  Sgk1  mRNA. These adaptive molecular responses of glucocorticoid-responsive gene expression and SGK1 in prefrontal cortex may contribute to mechanisms underlying behavioral responses to chronic ethanol exposure.

Ethanol Regulation of Serum Glucocorticoid Kinase 1 Expression in DBA2/J Mouse Prefrontal Cortex