Defense Date

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Michael Miles

Abstract

Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. Acute ethanol activates the hypothalamic pituitary adrenal (HPA) axis causing the release of adrenal glucocorticoid hormones, but following chronic ethanol the HPA axis is dysregulated in both humans and rodents. Thus, there is growing evidence that glucocorticoids might also modulate behavioral and molecular responses to ethanol. Previous microarray studies in the Miles’ laboratory have shown that the well-known glucocorticoid responsive gene, Serum and Glucocorticoid-regulated Kinase 1, Sgk1, is prominently up regulated by acute ethanol (2 g/kg) in the prefrontal cortex (PFC) of DBA/2J mice. Functionally, Sgk1 is an important focal point of intracellular signaling cross-talk through which the cell surface receptors, nuclear receptors, and cellular stress pathways converge to control many cellular processes including receptor or ion channel trafficking, cell proliferation and/or apoptotic responses. In the aforementioned microarray studies, Sgk1 was accompanied by a highly correlated group of genes, many of which are also known to respond to glucocorticoids. This suggests that stress-related signaling events might play an important role in ethanol regulation of the Sgk1 gene network. Prior work by others showed that Sgk1 plays an important role modulating synaptic plasticity occurring in memory. Based on these findings, it is hypothesized that glucocorticoids and glucocorticoid responsive genes are responsible for modulating acute and chronic cellular and behavioral responses to ethanol including locomotor activation and ethanol sensitization. In particular, because Sgk1 is regulated by ethanol, has a well-established role in learning and memory and is responsive to glucocorticoid signaling we hypothesize that Sgk1 is involved in modulating acute and chronic cellular and behavioral responses to ethanol including ethanol sensitization. Our results indicate that the induction of glucocorticoid responsive genes may play a role in regulating acute behavioral and cellular responses to ethanol. Adrenalectomized (ADX) and mifepristone (RU-486) both impaired acute ethanol (2 g/kg) induced locomotor activation in DBA/2J mice without affecting basal locomotor activity. ADX mice showed microarray gene expression changes in the PFC that significantly overlapped with acute ethanol-responsive gene sets derived by our prior microarray studies. Additionally, acute ethanol regulates Sgk1 transcription via glucocorticoid receptor binding to the Sgk1 promoter. Furthermore, increases in Sgk1 may occur to compensate for decreases in SGK1 protein and phosphorylation of SGK1 and its well-known target N-myc downstream-regulated gene 1 (NDRG1) is significantly increased 15 minutes following ethanol administration. Finally, Sgk1 intensifies and prolongs the expression phase of sensitization in D2 mice. Our studies suggest that ethanol’s activation of adrenal glucocorticoid release and subsequent glucocorticoid receptor activation may partially modulate ethanol’s acute locomotor activation in male D2 mice. Furthermore, adrenal glucocorticoid basal tone regulates PFC gene expression. A significant set of acute ethanol-responsive genes are regulated by adrenal glucocorticoid basal tone suggesting that glucocorticoid regulated PFC gene expression may be an important factor modulating acute behavioral responses to ethanol. Sgk1 is acutely regulated following ethanol administration by the glucocorticoid receptor binding to the Sgk1 promoter. Altogether, these results suggest a critical role for the hypothalamic pituitary adrenal axis and Sgk1 in regulating the acute and chronic cellular and behavioral responses to ethanol.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2013

Available for download on Wednesday, May 09, 2018

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