17β-Estradiol Is Required for the Sexually Dimorphic Effects of Repeated Binge-Pattern Alcohol Exposure on the HPA Axis during Adolescence

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.

Effects of Intermittent Alcohol Exposure on Emotion and Cognition: A Potential Role for the Endogenous Cannabinoid System and Neuroinflammation

“…These BECs were about 200 mg/dl and they are comparable to the concentrations reported in other studies conducted in adolescent Wistar rats using a model of binge-like drinking with i.p. injections of 3 g/kg, which reported 150–180 mg/dl 1 h postinjection (Przybycien-Szymanska et al, 2010 , 2012 ). Although our procedure raised plasma alcohol levels in a binge-like manner [binge drinking is indeed defined as heavy episodic drinking within a BEC of 80 mg/dl or higher (NIAAA, 2004 )], the alcohol administration was injected and it is possible that our model would yield higher alcohol doses than animals would consume voluntarily as it is expected in a binge drinking pattern (Spanagel, 2000 ).…”

Voluntary exercise decreases ethanol preference and consumption in C57BL/6 adolescent mice: Sex differences and hippocampal BDNF expression

“…This is based on the fact that reproductive hormones predominately regulate the HPA axis activity in females but not in males [25]. Furthermore, one study showed that 17β-estradiol, the predominant sex steroid hormone in females, is required for the sexually dimorphic effects of repeated alcohol exposure on the HPA axis during adolescence [54]. …”

The effects of abused drugs on adolescent development of corticolimbic circuitry and behavior

“…This change in corticosterone response is associated with an increase in CRH gene expression in the hypothalamus of male, but not female, rats exposed repeatedly to ethanol. Subsequent studies revealed this sex difference was due to a protective effect of estradiol on ethanol-induced upregulation of gene expression in females (Przybycien-Szymanska et al, 2012). When tested during adulthood, male rats pre-exposed to ethanol during adolescence, compared to saline-treated controls, exhibit reductions in basal corticosterone levels and exaggerated increases in corticosterone and CRH gene expression following ethanol challenge (Przybycien-Szymanska et al, 2011).…”