We recently uncovered the existence of a neural brain-testicular pathway that interferes with Leydig cell function independently of the pituitary. Specifically, we showed that within 5 min of their intracerebroventricular (icv) injection, corticotropin- releasing factor (CRF) or isoproterenol (ISO) blocked the stimulatory effect of human chorionic gonadotropin (hCG) on testosterone (T) release. Systemic alcohol injected 15 min prior to hCG exerted a similar effect. The ability of icv CRF or ISO, or of alcohol, to block the T response was neither mimicked nor reversed by iv pretreatment with a GnRH antagonist, indicating that their inhibitory effect was not due to low LH levels. In contrast, the icv injection of an adrenergic antagonist partially reversed the effect of icv ISO, icv CRF or systemic alcohol. These results support the existence of a neural pathway that rapidly inhibits Leydig cell function through an adrenergic mechanism. At present, neuromorphological evidence for this pathway is missing.
Under Specific Aim 1, we will use a viral transneuronal labeling method to identify sites in the central nervous system (CNS) that are involved in this pathway. This powerful neuroanatomical tool consists of the injection of pseudorabies virus (PRV) into the testis. Following replication, PRV is transported in a retrograde fashion to the perikarya of first-order neurons innervating the gonad, then to second-, third- and fourth-order neurons as the infection proceeds to further synaptically linked cell bodies. Virus-labeled neurons are identified by means of immunocytochemistry using polyclonal antibodies. Specificity of labeling will be determined by the ability of spermatic denervation and/or spinal cord T1 section, to eliminate PRV labeling in higher structures. After we have identified brain areas that belong to the proposed pathway, we will conduct functional experiments to determine its physiological importance.
Under Specific Aim 2, we will microinfuse CRF or ISO in selected brain areas. We anticipate that by activating the proposed inhibitory pathway, these treatments will decrease hCG-induced T secretion, compared to results obtained in animals infused with the vehicle.
Under Specific Aim 3, we will sever the spinal cord at the T1 level or lesion specific hypothalamic areas thought to be involved in the proposed pathway, to determine whether these procedures block the inhibitory effect of icv CRF or systemic alcohol on hCG-induced T secretion. These experiments will provide the first morphological and functional evidence of the existence of a multisynaptic neural pathway between the testes and the CNS, that is influenced by alcohol.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Noronha, Antonio
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Salk Institute for Biological Studies
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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
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; 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
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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