Abstract
BackgroundWe 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.ResultsAcute 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.ConclusionsThese 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.
Highlights
Alcohol dependence is a complex disease that develops over many years and includes cycles of withdrawal, craving, and relapse, acute responses to ethanol have predictive validity in terms of risk for high levels of ethanol intake in animal models and alcoholism in humans [1,2]
Using genomic studies we previously identified a significant over-representation of glucocorticoidresponsive genes, including Serum Glucocorticoid kinase 1 (Sgk1), responding to acute ethanol in prefrontal cortex (PFC) [12]
More recent studies from our laboratory showed that inhibition of glucocorticoid signaling by adrenalectomy or the glucocorticoid antagonist RU486 both impaired acute ethanol-induced locomotor activation, suggesting that glucocorticoid signaling may play a role in this behavioral response [15]
Summary
Alcohol dependence is a complex disease that develops over many years and includes cycles of withdrawal, craving, and relapse, acute responses to ethanol have predictive validity in terms of risk for high levels of ethanol intake in animal models and alcoholism in humans [1,2]. This activating phosphorylation had functional consequences, as suggested by increased phosphorylation of the known SGK1 target, N-myc downstream-regulated gene 1 (NDRG1). Conclusions: These results suggest that HPA axis and glucocorticoid receptor signaling mediate acute ethanol induction of Sgk transcription in mouse prefrontal cortex. Acute ethanol causes complex changes in SGK1 protein expression and activity Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of Sgk 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
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