Prenatal ethanol exposure alters the responsiveness of the rat hypothalamic-pituitary-adrenal axis to nitric oxide

Background: Prenatal alcohol exposure is known to cause hyperactivity of the mature offspring's hypothalamic-pituitary-adrenal (HPA) axis. We have recently shown that hypothalamic neurons that produce corticotropin-releasing factor (CRF), the peptide that represents the major adrenocorticotropin hormone (ACTH) secretagogue, display increased responses to various stimuli in prenatal alcohol-exposed (E), compared to control (C) rats. CRF-producing perikarya are regulated, in part, by nitric oxide (NO), a signaling molecule whose function is also modified by prenatal alcohol exposure. The present investigation was therefore undertaken to test the hypothesis that prenatal alcohol exposure is associated with alterations in NO-stimulated ACTH secretion. Methods: Adult male and female Sprague-Dawley rats exposed to alcohol in utero were injected intracerebroventricularly (icv) with the vehicle or the NO donor 3-morpholino-sydnonimine (SIN-1; 20 or 50 mug). ACTH levels were measured in blood samples collected from indwelling jugular carmulae at 15, 30 and 45 min following injection. Brains were obtained 45 and 90 min after SIN-1 injection and processed for in situ hybridization. Results: Compared to males, both C and E females exhibited a significantly (p < 0.01) larger ACTH response to SIN-1 (20 mug). Prenatal alcohol treatment enhanced SIN-1-induced ACTH release in all E animals, but this difference only reached statistical significance (p < 0.01) in males. This prenatal influence was also observed in the significantly (p < 0.01) larger SIN-1-induced increase in transcripts for the immediate early gene nerve growth factor induced protein B (NGFI-B) in the paraventricular nucleus (PVN) of the males', but not females' hypothalamus. Conclusions: The ability of increased brain NO levels to release ACTH and stimulate PVN neuronal activity is enhanced in adult male rats exposed to alcohol prenatally. These data support the hypothesis that alterations in HPA axis activity in adult offspring of alcohol-exposed dams may be related to changes in hypothalamic responsiveness to NO.