Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress

Abstract

Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of mental health problems, including substance use disorders (SUD). The hypothalamic-pituitary-adrenal (HPA) and dopamine systems have overlapping neurocircuitries and are both implicated in SUD. PAE alters both HPA and dopaminergic activity and regulation, resulting in increased HPA tone and an overall reduction in tonic dopamine activity. However, effects of PAE on the interaction between HPA and dopamine (DA) systems have not been investigated. The present study examined PAE effects on basal regulation of central stress and dopamine systems in key brain regions where these systems intersect. Adult Sprague-Dawley male and female offspring from prenatal alcohol-exposed (PAE), pairfed (PF), and ad libitum-fed control (C) groups were subjected to chronic variable stress (CVS) or remained as a no stress (non-CVS) control group. Corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and DA receptor (DA-R) expression were measured under basal conditions 24 hours following the end of CVS. We show, for the first time, that regulation of basal HPA and DA systems, and likely, HPA-DA interactions, are altered differentially in males and females by PAE and CVS. PAE augmented the typical attenuation in weight gain during CVS in males and caused increased weight loss in females. Increased basal corticosterone levels in control, but not PAE, females suggest that PAE alters the profile of basal hormone secretion throughout CVS. CVS downregulated basal CRH mRNA in the prefrontal cortex and throughout the bed nucleus of the stria terminalis (BNST) in PAE females but only in the posterior BNST of control females. PAE males and females exposed to CVS exhibited more widespread upregulation of basal mineralocorticoid receptor (MR) mRNA throughout the hippocampus, and an attenuated decrease in DA-R expression throughout the nucleus accumbens and striatum compared to CVS-exposed control males and females. Overall, these findings enhance our understanding of PAE effects on the cross-talk between HPA and DA systems, and provide insight into possible mechanisms underlying mental health problems that are related to stress and DA signaling, including SUD, which have a high prevalence among individuals with FASD.

Prenatal alcohol exposure and adolescent stress increase sensitivity to stress and gonadal hormone influences on cognition in adult female rats

“…Although consistent with the literature, our current findings are notable owing to the relatively mild stressors incorporated into the CMS regimen, and provide a longitudinal approach to begin to elucidate the possible relationship between PAE, adolescent experience, and dysregulated HPA function on cognitive performance in adulthood. Of note, these relationships may not be unique to adolescent experiences, as we have shown previously that basal corticosterone levels are increased in control, but not PAE, females following CMS exposure in adulthood, suggesting that PAE may blunt the normal change in basal CORT levels during CMS in adulthood as well (Uban et al, 2013). Moreover, chronic stress may affect males and females differently.…”

“…In some instances, females may be more sensitive to the effects of chronic stress in terms of hormonal stress response, showing greater changes in hormone secretion after being exposed to the same stressors as males (Galea et al, 1997, Cameron, 2004). Relevant to this point, in contrast to the differences in basal CORT levels observed in PAE compared to control females, Uban and colleagues (Uban et al, 2013) found no differences in basal CORT levels between PAE and control males following CMS, highlighting the importance of sex differences in the investigation of PAE-related responses to early and later life environmental stressors.…”

Effect of repeated alcohol exposure during the third trimester-equivalent on messenger RNA levels for interleukin-1β, chemokine (C–C motif) ligand 2, and interleukin 10 in the developing rat brain after injection of lipopolysaccharide

“…Given the sexually dimorphic effects of PAE (Goodlett and Peterson, 1995; Uban et al, 2013; Weinberg et al., 2008), as well as the striking gender differences in microglia colonization during development (Schwarz et al, 2012), we included both males and females in this study. In the DG, we detected no difference in the LPS-induced pro-inflammatory response between males and females.…”

Fetal alcohol spectrum disorders and cognitive functions of young children

“…Antenatal ethanol exposure affects the interrelation of the dopaminergic system with the hypothalamic-pituitary-adrenal (HPA) axis. This effect is sex dependent (Uban et al, 2013). Specifically, males are characterized by low testosterone levels, which may reduce their capacity to control the HPA axis responsiveness to stimuli, something that is not reported among females (Uban et al, 2013).…”