Abstract

EXCEED THE SPACE PROVIDED. The ability of prenatal alcohol to cause hyperactivity of the mature offspring hypothalamic-pituitary-adrenal (HPA) axis is well established, but the mechanisms mediating this phenomenon remain poorly understood. Levels of nitric oxide (NO) and catecholamines, both of which stimulate the HPA axis, are reportedly altered by prenatal alcohol.
Under Specific Aim 1, we will therefore investigate the role of these secretagogues in mediating the influence of the drug. Specifically, we will determine if prenatal alcohol alters basal levels of NO and/or norepinephrine and dopamine; whether the stimulatory effect that NO and catecholamines exert on the HPA axis of the mature offspring is modified; and whether prenatal alcohol alters the ontogeny of hypothalamic corticotropin releasing factor (CRF).
Under Specific Aim 2, we will extend these studies to the role of specific receptors for CRF, the hypothalamic peptide that is the primary regulator of the HPA axis. Specifically, we will test the hypothesis that CRF receptors type 1, but not type 2 are indispensable in allowing the influence of prenatal alcohol to be exerted on the offspring' HPA axis. These experiments will be carried out in mutant mice lacking the gene for these receptors. Finally, Specific Aim 3 will be devoted to continue our studies of the mechanisms through which postnatal alcohol alters HPA axis activity in rats. We have shown that exposure to this drug blunted this axis' response to a variety of stressors. Very recently we also showed that alcohol modified the ability of these stressors to upregulate NO levels. In the present grant we will identify the type of NO synthase isoform(s) that mediate(s) the influence of alcohol on nitrergic pathways, and test the hypothesis that alcohol-induced changes in the functional interactions between CRF and NO represent important mechanisms modulating the influence of this drug. PERFORMANCE SITE ========================================Section End===========================================

  Funding Agency

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 #
4R37AA008924-15
Application #
6858038
Study Section
Special Emphasis Panel (NSS)
Program Officer
Grandison, Lindsey
Project Start
1991-04-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
15
Fiscal Year
2005
Total Cost
$575,792
Indirect Cost

  Institution

Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

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
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
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
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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