Prenatal alcohol exposure increases vulnerability to stress and anxiety-like disorders in adulthood

Abstract

Children and adults with fetal alcohol spectrum disorder (FASD) have elevated rates of depression and anxiety disorders compared to control populations. The effects of prenatal alcohol exposure (PAE) on anxiety, locomotor activity, and hormonal reactivity in male and female rats tested on the elevated plus maze (EPM), a task commonly used to assess anxiety-like behaviors in rodents, were examined. Pregnant dams were assigned to PAE, pair-fed (PF), or ad libitum-fed control (C) groups. At adulthood, half of all male (N= 60) and female (N= 60) PAE, PF, and C offspring were exposed to 10 days of chronic mild stress (CMS); the other half remained undisturbed. Animals were then tested on the EPM, and blood collected 30 min posttest for analysis of corticosterone (CORT), testosterone, estradiol, and progesterone. Overall, CMS exposure produced a significant anxiogenic profile. Moreover, CMS increased anxiety-like behavior in PAE males and females compared to controls and eliminated the locomotor hyperactivity observed in nonstressed PAE females. CMS also increased post-EPM CORT, testosterone, and progesterone levels in all groups, with CORT and progesterone levels significantly higher in PAE than in C females. By contrast, CMS selectively lowered estradiol levels in PAE and PF, but not C, females. CMS exposure reveals sexually dimorphic behavioral and endocrine alterations in PAE compared to C animals. Together, these data suggest the possibility that fetal reprogramming of hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) systems by alcohol may underlie, at least partly, an enhanced susceptibility of fetal alcohol-exposed offspring to depression/anxiety-like disorders in adulthood.

Figure 1

Effect of prenatal treatment, sex, and chronic mild stress (CMS) on (A) percent time spent in the open arms (%), and (B) frequency of total (full + partial) open arm entries on the elevated plus maze (EPM). Black bars represent prenatal alcohol exposeure (PAE), hatched bars represent pair-fed (PF), white bars represent control (C) animals. (*) Denotes significantly different from the Non-CMS group, P < −.05. (#) Denotes significantly different from other prenatal groups, P < .05. (^) Denotes significant differences between sexes, P < .05. n’s = 7–10 in each condition.

Figure 2

Effect of prenatal treatment, sex, and chronic mild stress (CMS) on (A) frequency of total arm entries, and (B) total distance traveled (cm) on the elevated plus maze (EPM). Black bars represent prenatal alcohol exposed (PAE), hatched bars represent pair-fed (PF), white bars represent control (C) animals. (*) Denotes significantly different from the Non-CMS group, P < .05. (#) Denotes significantly different from other prenatal groups, P < .05. (^) Denotes significant differences between sexes, P < .05. n’s = 7–10 in each condition.

Figure 3

Effect of prenatal treatment, sex, and chronic mild stress (CMS) on plasma corticosterone levels (µg/dL) 30-min post-elevated plus maze (EPM) testing. Black bars represent prenatal alcohol exposed (PAE), hatched bars represent pair-fed (PF), white bars represent control (C) animals. (*) Denotes significantly different from the Non-CMS group, P < .05. (#) Denotes significantly different from other prenatal groups, P < .05. n’s = 7–10 for each condition.

Figure 4

Effect of prenatal treatment and chronic mild stress (CMS) on plasma levels of (A) testosterone, (B) estradiol, and (C) progesterone (ng/mL) post-elevated plus maze (EPM) testing in male (A) and female (B and C) rats. Black bars represent prenatal alcohol exposed (PAE), hatched bars represent pair-fed (PF), white bars represent control (C) animals. (*) Denotes significantly different from the Non-CMS group, P < .05. (#) Denotes significantly different from other prenatal groups, P < .05. n’s = 7–10 for each condition.