Novel role of adrenergic neurons in the brain stem in mediating the hypothalamic–pituitary axis hyperactivity caused by prenatal alcohol exposure

Abstract

Exposure to alcohol during embryonic development leads to changes in the hypothalamic–pituitary–adrenal (HPA) axis such that adult offspring release more adrenocorticotrophic hormone (ACTH) than controls when exposed to stress. In the present work, we tested the hypothesis that changes in the activity of the catecholaminergic system modulate, at least in part, this upregulation of the HPA axis. Pregnant Sprague–Dawley rats were exposed to alcohol 6 h daily during gestation days 7–18 using the vapor chamber model, which generated mean blood alcohol levels of 188.6±10 mg/dl. All experiments were performed on 2 to 3-month-old offspring. We first measured the ACTH response to i.c.v. injection of adrenergic receptor agonists. In rats exposed to footshocks, we then investigated the activity of corticotrophin-releasing factor (CRF) as well as indexes of catecholamine ir, namely tyrosine hydroxylase (TH) immunopositive neurons in the paraventricular nucleus (PVN), TH immunopositive neurons in the locus coeruleus, and phenylethanolamine N-methyltransferase (PNMT) immunopositive neurons in the brain stem. While adult females exposed to alcohol during fetal development (FAE) displayed the expected enhanced ACTH response to stress, there were no significant differences in response to adrenergic receptor agonists or in shock-induced CRF/TH ir and neuronal activity, as determined by c-fos colocalization. In contrast, FAE female offspring exposed to footshocks showed a significant increase in the activity of adrenergic neurons in the C1 region of the brain stem, a population of cells that project to the PVN. Collectively, these results suggest that while FAE-induced hyperactivity of the HPA axis is not accompanied by significant changes in PVN CRF or TH-ir neurons, it is characterized by an upregulation of C1 adrenergic neurons of the brain stem. This novel finding should lead to the functional characterization of this brain region in the FAE model.