Exposure to alcohol alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Work carried out in our laboratory as well as other's indicates that prenatal alcohol exposure augments HPA axis activity in mature offspring, while animals chronically exposed to the drug for the first time in adulthood display blunted HPA axis responses. The purpose of this proposal is to investigate some of the mechanisms responsible for these effects. First, we will focus on nitric oxide (NO), a gaseous neurotransmitter that, as we recently reported, significantly stimulates levels of corticotropin releasing factor (CRF) and vasopressin (VP) in the hypothalamus. Specifically, we will test the hypothesis that prenatal alcohol alters (a) hypothalamic levels of NO and NO synthase (NOS), the enzyme responsible for NO formation, (b) the CRF and/or VP neuronal response to NO donors, and (c) the physiological role played by NO, which will be studied with NOS antagonists (Specific Aim 1). Second, we will test the hypothesis that alcohol-induced increases in hypothalamic CRF levels, through activation of a hypothalamic feed forward mechanism previously reported by our laboratory, participates in the hyperactive HPA axis that is the hallmark of prenatal alcohol (Specific Aim 2). At present, there is no information regarding the effect of prenatal alcohol exposure on the HPA axis of murine offspring. As a first step, we will therefore develop a murine model of prenatal alcohol treatment and investigate HPA axis responses in wild-type mice born to dams exposed to alcohol during gestation. These experiments will rely on an automated system that was recently developed in our laboratory, and that allows us to deliver intermittent amounts of alcohol vapors that are customized for each animal. Once the parameters of this new model are established, we will investigate the role of alcohol-induced changes in CRF levels, by exposing to alcohol vapors pregnant wild-type mice and mice lacking the gene for CRF receptors type 1 or 2, and comparing the HPA axis of their offspring. The final part of our proposal will focus on the hypothesis that long-term alcohol vapor treatment of adult rats decreases hypothalamic NO production, thereby contributing to the blunted HPA axis activity that characterizes these animal (Specific Aim 3). All the proposed experiments rely on cutting-edge methodology that was developed in our laboratory, as well as on recent concepts of brain regulation by NO. These studies will provide important information regarding effects of alcohol that are well documented in animal models as well as in humans, but for which mechanisms remain poorly understood.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA008924-11
Application #
6371333
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Lucas, Diane
Project Start
1991-04-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
11
Fiscal Year
2001
Total Cost
$490,650
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Rivier, Catherine (2014) Role of hypothalamic corticotropin-releasing factor in mediating alcohol-induced activation of the rat hypothalamic-pituitary-adrenal axis. Front Neuroendocrinol 35:221-33
Lee, S; Craddock, Z; Rivier, C (2011) Brain stem catecholamines circuitry: activation by alcohol and role in the hypothalamic-pituitary-adrenal response to this drug. J Neuroendocrinol 23:531-41
Choi, I Y; Lee, S; Rivier, C (2008) Novel role of adrenergic neurons in the brain stem in mediating the hypothalamic-pituitary axis hyperactivity caused by prenatal alcohol exposure. Neuroscience 155:888-901
Lee, Soon; Choi, Irene; Kang, Sang et al. (2008) Role of various neurotransmitters in mediating the long-term endocrine consequences of prenatal alcohol exposure. Ann N Y Acad Sci 1144:176-88
Lee, Soon; Rivier, Catherine (2005) Role played by hypothalamic nuclear factor-{kappa}B in alcohol-mediated activation of the rat hypothalamic-pituitary-adrenal axis. Endocrinology 146:2006-14
Li, Zhongqi; Kang, Sang Soo; Lee, Soon et al. (2005) Effect of ethanol on the regulation of corticotropin-releasing factor (CRF) gene expression. Mol Cell Neurosci 29:345-54
Kang, Sang Soo; Cole, Maury; Lee, Soon et al. (2004) Development of individual alcohol inhalation chambers for mice: validation in a model of prenatal alcohol. Alcohol Clin Exp Res 28:1549-56
Seo, Dong O; Lee, Soon; Rivier, Catherine (2004) Prolonged exposure to intermittent alcohol vapors decreases the ACTH as well as hypothalamic nitric oxide and cytokine responses to endotoxemia. Alcohol Clin Exp Res 28:848-54
Seo, Dong Ook; Rivier, Catherine (2003) Interaction between alcohol and nitric oxide on ACTH release in the rat. Alcohol Clin Exp Res 27:989-96
Lee, Soon; Blanton, Cynthia A; Rivier, Catherine (2003) Prenatal ethanol exposure alters the responsiveness of the rat hypothalamic-pituitary-adrenal axis to nitric oxide. Alcohol Clin Exp Res 27:962-9

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