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Ethanol regulation of serum glucocorticoid kinase 1 expression in DBA2/J mouse prefrontal cortex.

Costin BN, Dever SM, Miles MF - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA.

ABSTRACT

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.

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Serum corticosterone levels following ethanol sensitization.Behavioral sensitization followed by corticosterone quantification. Panels show: (a) Acute and sensitized locomotor response (cm/10 min.) following saline (SS, ES) or ethanol (EE, SE) administration. * p < 0.05 versus SS and ES groups, # p < 0.05 versus SE, ES and SS groups; (b) Corticosterone levels 1 hour following acute and chronic ethanol administration. * p < 0.05 versus SS, EE, and ES groups.
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pone-0072979-g004: Serum corticosterone levels following ethanol sensitization.Behavioral sensitization followed by corticosterone quantification. Panels show: (a) Acute and sensitized locomotor response (cm/10 min.) following saline (SS, ES) or ethanol (EE, SE) administration. * p < 0.05 versus SS and ES groups, # p < 0.05 versus SE, ES and SS groups; (b) Corticosterone levels 1 hour following acute and chronic ethanol administration. * p < 0.05 versus SS, EE, and ES groups.

Mentions: Sgk1 is a well-known glucocorticoid responsive gene and it is known that animals and human alcoholics show a blunted HPA axis while drinking and upon withdrawal. Because Sgk1 levels were not regulated in animals following ethanol sensitization despite normal levels of Nr3c1 expression, we hypothesized that corticosterone levels may be blunted in animals chronically treated with ethanol (EE animals). We sensitized animals to ethanol and collected blood one hour following behavioral testing to measure corticosterone levels across SS, SE, EE and Ethanol-Saline (ES) treated animals. In evaluating the behavioral response to ethanol, there was again evidence of strong locomotor sensitization. A one-way ANOVA showed an overall effect of treatment (F3,15= 159.67, p < 0.01) (Figure 4a). Post-hoc analysis revealed that EE treated animals showed a significantly greater locomotor response compared to SS, SE, and ES treated animals. In addition, SE treated animals showed a greater locomotor response compared to SS and ES treated animals. In evaluating corticosterone levels at one hour after injections of SS, SE, EE and ES mice, a one-way ANOVA showed an overall significant effect of treatment (F3,15= 47.37, p < 0.01) (Figure 4b). Post-hoc analysis revealed that SE animals showed greater corticosterone levels than SS, EE and ES indicating that corticosterone levels were blunted with chronic ethanol treatment.


Ethanol regulation of serum glucocorticoid kinase 1 expression in DBA2/J mouse prefrontal cortex.

Costin BN, Dever SM, Miles MF - PLoS ONE (2013)

Serum corticosterone levels following ethanol sensitization.Behavioral sensitization followed by corticosterone quantification. Panels show: (a) Acute and sensitized locomotor response (cm/10 min.) following saline (SS, ES) or ethanol (EE, SE) administration. * p < 0.05 versus SS and ES groups, # p < 0.05 versus SE, ES and SS groups; (b) Corticosterone levels 1 hour following acute and chronic ethanol administration. * p < 0.05 versus SS, EE, and ES groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750005&req=5

pone-0072979-g004: Serum corticosterone levels following ethanol sensitization.Behavioral sensitization followed by corticosterone quantification. Panels show: (a) Acute and sensitized locomotor response (cm/10 min.) following saline (SS, ES) or ethanol (EE, SE) administration. * p < 0.05 versus SS and ES groups, # p < 0.05 versus SE, ES and SS groups; (b) Corticosterone levels 1 hour following acute and chronic ethanol administration. * p < 0.05 versus SS, EE, and ES groups.
Mentions: Sgk1 is a well-known glucocorticoid responsive gene and it is known that animals and human alcoholics show a blunted HPA axis while drinking and upon withdrawal. Because Sgk1 levels were not regulated in animals following ethanol sensitization despite normal levels of Nr3c1 expression, we hypothesized that corticosterone levels may be blunted in animals chronically treated with ethanol (EE animals). We sensitized animals to ethanol and collected blood one hour following behavioral testing to measure corticosterone levels across SS, SE, EE and Ethanol-Saline (ES) treated animals. In evaluating the behavioral response to ethanol, there was again evidence of strong locomotor sensitization. A one-way ANOVA showed an overall effect of treatment (F3,15= 159.67, p < 0.01) (Figure 4a). Post-hoc analysis revealed that EE treated animals showed a significantly greater locomotor response compared to SS, SE, and ES treated animals. In addition, SE treated animals showed a greater locomotor response compared to SS and ES treated animals. In evaluating corticosterone levels at one hour after injections of SS, SE, EE and ES mice, a one-way ANOVA showed an overall significant effect of treatment (F3,15= 47.37, p < 0.01) (Figure 4b). Post-hoc analysis revealed that SE animals showed greater corticosterone levels than SS, EE and ES indicating that corticosterone levels were blunted with chronic ethanol treatment.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus