Abstract
Alcohol consumption during adolescence has long-term sexually dimorphic effects on anxiety behavior and mood disorders. We have previously shown that repeated binge-pattern alcohol exposure increased the expression of two critical central regulators of stress and anxiety, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), in adolescent male rats. By contrast, there was no effect of alcohol on these same genes in adolescent females. Therefore, we tested the hypothesis that 17β-estradiol (E2), the predominant sex steroid hormone in females, prevents alcohol-induced changes in CRH and AVP gene expression in the paraventricular nucleus (PVN) of the hypothalamus. To test this hypothesis, postnatal day (PND) 26 females were ovariectomized and given E2 replacement or cholesterol as a control. Next, they were given an alcohol exposure paradigm of 1) saline alone, 2) acute (single dose) or 3) a repeated binge-pattern. Our results showed that acute and repeated binge-pattern alcohol treatment increased plasma ACTH and CORT levels in both E2- and Ch-treated groups, however habituation to repeated binge-pattern alcohol exposure was evident only in E2-treated animals. Further, repeated binge-pattern alcohol exposure significantly decreased CRH and AVP mRNA in Ch-, but not E2-treated animals, which was consistent with our previous observations in gonad intact females. We further tested the effects of E2 and alcohol treatment on the activity of the wild type CRH promoter in a PVN-derived neuronal cell line. Alcohol increased CRH promoter activity in these cells and concomitant treatment with E2 completely abolished the effect. Together our data suggest that E2 regulates the reactivity of the HPA axis to a repeated stressor through modulation of the habituation response and further serves to maintain normal steady state mRNA levels of CRH and AVP in the PVN in response to a repeated alcohol stressor.
Highlights
Dimorphic patterns of addictive behavior emerge during adolescence and often persist in adulthood
We showed that adolescent repeated binge-pattern alcohol exposure altered the central expression of corticotrophin-releasing hormone (CRH) and AVP mRNA in the paraventricular nucleus (PVN), the major brain region involved in modulating the physiological stress response [11]
The key novel findings in this study demonstrate that the predominant female sex hormone, E2, was partly responsible for mediating the sex-specific effects of EtOH on the hypothalamo-pituitary adrenal (HPA) axis, but it was not the only contributing factor
Summary
Dimorphic patterns of addictive behavior emerge during adolescence and often persist in adulthood. In early adolescence (ages 12–17), the amount and frequency of alcohol consumption does not differ between boys and girls, yet it becomes markedly skewed in young adults with males consuming significantly more alcohol than females [1]. Consumption of alcohol for individuals between the ages of 18 and 25 tends to be excessive and sporadic (‘‘binge’’ drinking) which leads to increased risk-taking behavior [1,2,3,4,5]. One possible explanation for these sex differences is that early experimentation with alcohol (i.e. 12–16 years old) differentially activates the stress response, and/or centrally-mediated reward systems, resulting in divergent behavioral patterns that emerge in late adolescents/ young adults. An acute psychological or physical stressor activates the hypothalamo-pituitary adrenal (HPA) axis
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