We recently uncovered a neural pathway between the hypothalamus and the testes that decreases testosterone (T) independently of pituitary LH, changes in testicular LH receptors or blood flow, and various circulating factors. We showed that the intragastric (ig) injection of alcohol inhibits Leydig cell activity responsiveness to gonadotropins in part through activation of this pathway, and thus independently of peripheral mechanisms. This effect is mimicked by the intracerebroventricular (icv) injection of a small (5 mu l) volume of alcohol that does not cause neuronal damage or leak to the periphery, but quickly and significantly blunts the T response to human chorionic gonadotropin (hCG).
Under Specific Aim 1, we will further characterize this pathway by combining the intratesticular injection of the retrograde transganglionic tracer pseudorabies virus with the Fos response that is elicited in various brain regions by the icv injection of alcohol.
Specific Aim 2 will focus on the testicular messengers through which alcohol inhibits Leydig cell activity, which has been a long-standing and unresolved issue. Specifically, we will identify some of the molecules whose synthesis is stimulated in the testes by the ig or icv injection alcohol, and that modulate the ensuing loss of Leydig cell activity. We will then turn to hypotheses related to the physiological importance of the proposed neural pathway.
Under Specific Aim 3, we will investigate the role of this circuit in mediating the inhibitory influence of alcohol on sexual maturation, then compare this role to that of peripherally-mediated mechanisms such as direct testicular effects exerted by circulating levels of the drug. Finally under Specific Aim 4, we will explore a novel interaction that we recently uncovered between alcohol and other stressors. Specifically, we showed that prior exposure to a modest dose of alcohol, injected icv or ig, increases the ability of mild electrofootshocks to inhibit Leydig cell activity. Here we will test the hypothesis that alcohol exerts this effect by augmenting the effect of stress-related signals on the hypothalamic-testicular pathway. Collectively, these studies will advance our understanding of the effects of alcohol on male reproductive functions and the mechanisms that mediate them.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012810-08
Application #
7236246
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grandison, Lindsey
Project Start
2000-09-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
8
Fiscal Year
2007
Total Cost
$397,241
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Lee, Soon; Braden, Brian; Kang, Sang Soo et al. (2011) Urocortins are present in the rat testis. Neuropeptides 45:131-7
Allen, Camryn D; Waser, Beatrice; Korner, Meike et al. (2011) Neuropeptide Y acts within the rat testis to inhibit testosterone secretion. Neuropeptides 45:55-61
Rivier, Catherine L (2008) Urocortin 1 inhibits rat leydig cell function. Endocrinology 149:6425-32
James, P; Rivier, C; Lee, S (2008) Presence of corticotrophin-releasing factor and/or tyrosine hydroxylase in cells of a neural brain-testicular pathway that are labelled by a transganglionic tracer. J Neuroendocrinol 20:173-81
Selvage, Daniel J; Parsons, Loren; Rivier, Catherine (2006) Role played by brainstem neurons in regulating testosterone secretion via a direct neural pathway between the hypothalamus and the testes. Endocrinology 147:3070-5
Herman, Melissa; Rivier, Catherine (2006) Activation of a neural brain-testicular pathway rapidly lowers Leydig cell levels of the steroidogenic acute regulatory protein and the peripheral-type benzodiazepine receptor while increasing levels of neuronal nitric oxide synthase. Endocrinology 147:624-33
Herman, Melissa; Kang, Sang Soo; Lee, Soon et al. (2006) Systemic administration of alcohol to adult rats inhibits leydig cell activity: Time course of effect and role of nitric oxide. Alcohol Clin Exp Res 30:1479-91
Selvage, Daniel J; Hales, D Buchanan; Rivier, Catherine L (2004) Comparison between the influence of the systemic and central injection of alcohol on Leydig cell activity. Alcohol Clin Exp Res 28:480-8
Selvage, Daniel J; Lee, Soon Y; Parsons, Loren H et al. (2004) A hypothalamic-testicular neural pathway is influenced by brain catecholamines, but not testicular blood flow. Endocrinology 145:1750-9
Selvage, Daniel J; Rivier, Catherine (2003) Importance of the paraventricular nucleus of the hypothalamus as a component of a neural pathway between the brain and the testes that modulates testosterone secretion independently of the pituitary. Endocrinology 144:594-8

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