Date of Award

2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Binge alcohol (EtOH) exposure in adolescence is a fundamental health concern. In 2005, over 20% of teenagers between ages 15 and 17 reported binge drinking behavior within a one month period preceding the survey (Dept. of Health and Human Services: Substance Abuse and Mental Health Services Administration). Binge drinking is defined as consuming enough alcohol within a 2.0 h period to bring blood alcohol concentration above 0.08%. In the adolescent population, this type of alcohol exposure tends to be repeated. In adults, alcohol abuse has been correlated with increased incidence of mood disorders and these disorders are characterized by dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, a three tiered biological system that mediates physiological stress response. Corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) localized in the paraventricular nucleus (PVN) of the hypothalamus are the major neuropeptides involved in modulating HPA axis responses to stress. Corticosterone (CORT) in rodents, and cortisol in humans, is a major glucocorticoid hormone released into the circulation upon activation of the HPA axis. Puberty is a period during which extensive maturation occurs, yet our knowledge of the nurobiological consequences of binge EtOH exposure during this time period is severely limited. I sought to investigate the neuroendocrine consequences of EtOH exposure during pubertal maturation and tested the hypothesis that EtOH exposure during puberty has long lasting detrimental consequences for a proper maturation of the HPA axis. My data revealed that repeated binge-pattern EtOH exposure resulted in a sex specific dysregulation of the HPA axis in pubertal rats. This was marked by an increase in the expression of CRH and AVP mRNA in the male, but not female, PVN. Notably, in both sexes, both single and repeated binge EtOH exposures resulted in increased circulating CORT levels and habituation effects. These results suggested that repeated binge-like EtOH exposure differentially dysregulated the HPA axis in males compared to females (Przybycien-Szymanska et al., AJP Endocrin. and Metabol., 2010). My data further showed that the sex steroid hormone, 17β-estradiol, is required for the maintenance of steady state levels of CRH and AVP mRNA in the PVN of pubertal female rats and for the habituation effects observed in CORT responses after repeated binge-pattern EtOH exposure. Most striking, these results showed that in males, binge-pattern EtOH exposure during puberty resulted in the dysregulation of adult HPA axis. This was evidenced by 1) increased adult basal levels of CRH mRNA in the PVN and lower basal circulating CORT levels, 2) differential patterns of CRH and AVP mRNA expression in the PVN after subsequent EtOH exposures in adulthood, 3) enhanced circulating CORT increase after single or repeated binge-like exposures in adulthood, 4) lack of habituation in CORT response after adult repeated binge pattern EtOH exposure (Przybycien-Szymanska et al., PLoS One, 2011). In addition, I investigated the molecular mechanisms involved in the observed EtOH-induced increase in the CRH mRNA in the PVN. Increased gene expression correlates closely with increased gene promoter activity; therefore I tested whether EtOH affects CRH promoter activity and whether glucocorticoid negative feedback at the promoter was dysregulated by EtOH. My data showed that EtOH exerts a biphasic effects on the activity of the CRH promoter and these effects are blocked by glucocorticoid receptor (GR) antagonist and deletion of glucocorticoid response element site (a binding site for GR) on CRH promoter. These results indicated that EtOH dysregulates functioning of the HPA axis by interfering with normal negative glucocorticoid feedback mechanism exerted on CRH promoter. Moreover, I showed that 17β-estradiol prevented the EtOH-induced increase in CRH promoter activity supporting a role of this hormone in the sexually dimorphic changes of CRH mRNA in the PVN after EtOH exposure. In conclusion, my data showed that binge-pattern EtOH exposure during puberty has long lasting effects on the HPA axis. These effects are manifested by alterations in PVN expression of neuropeptides involved in modulating stress responses and glucocorticoid hormone signaling. These effects are caused by EtOH-induced dysregulation of glucocorticoid negative feedback normally exerted at the level of the gene promoter in the PVN and may lead to increased risk for mood disorders in adulthood.

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