EFFECTS OF ALCOHOL ON CENTRAL NEUROENDOCRINE SYSTEMS

酒精对中枢神经内分泌系统的影响

• 批准号: 6563147
• 负责人: CATHERINE L RIVIER
• 金额: $ 25.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563147
• 关键词: adrenocorticotropic hormone; behavioral /social science research tag; corticosterone; corticotropin releasing factor; embryo /fetus toxicology; endocrine pharmacology; ethanol; experimental brain lesion; gender difference; gene expression; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; immunocytochemistry; laboratory mouse; laboratory rat; neuroendocrine system; neuropharmacology; pharmacogenetics; pituitary gonadal axis; regulatory gene; reproductive development; stress

We have recently observed that rats exposed to alcohol for three consecutive days via indwelling intragastric cannulae (Model A) showed the expected initial rise in plasma ACTH and corticosterone levels, but that upon a re-challenge with the drug 3-12 days later, these hormone responses were significantly blunted. Under Specific Aim 1, we will test hypothesis related to the mechanisms responsible for the decreased HPA axis in this model of short-term alcohol treatment. We will first determine whether pituitary responsiveness to CRF and/or vasopressin is reduced. If this is the case, we will test the hypothesis that steady-state MRNA levels of pituitary CRF-R1 and/or POMC are decreased, and/or that the pituitary is more sensitive to glucocorticoid feedback. Using transcript levels of the immediate early gene NGFI-B, we will also determine whether hypothalamic neuronal activation is blunted during a second alcohol challenge. If they are reduced, we will test the hypothesis that this is accompanied by decreased CRF synthesis in the hypothalamus, possibly via increased sensitivity to CRF neurons to glucocorticoid feedback. In parallel studies, we will also use a model of chronic alcohol treatment (Model B), in which rats are exposed to intermittent alcohol vapors for 2 weeks, then re-challenged with this drug following a period of protracted abstinence. We will first determine whether animals of Model B also show neuroendocrine tolerance when re-exposed to alcohol or whether, as observed with other long-term stress paradigms, they will exhibit an exacerbated response of their HPA axis. In either case, the mechanisms responsible for these changes will be investigated. Experiments carried out under Specific Aim 2, on the other hand, will use knock-out mice to investigate the importance of CRF and its receptors on the response of the HPA axis to alcohol. In CRF-deficient mice, we will test the hypothesis that CRF is the sole mediator of this response. In mice homozygous for a null CRF-R1 allele, we will test the hypothesis that pituitary and/or hypothalamic CRF-R1 participate in alcohol-induced ACTH release. Finally in CRF-R/2 knock-out mice, we will test the hypothesis that pituitary and/or hypothalamic CRF-R2 are not necessary for this ACTH response.

我们最近观察到暴露于酒精的大鼠三只 连续通过留置胃内套管（A模型）显示了 预计血浆ACTH和皮质酮水平的初始升高，但 3-12天后，在使用药物重新挑战时，这些激素反应 显着钝了。在特定目标1下，我们将检验假设 与导致HPA轴减少的机制有关 短期酒精治疗的模型。我们将首先确定是否 对CRF和/或加压素的垂体反应能力降低。如果是 案例，我们将测试稳态mRNA水平的假设 垂体CRF-R1和/或POMC减少，/或垂体为/或 对糖皮质激素反馈更敏感。使用成绩单级别 立即早期基因NGFI-B，我们还将确定下丘脑是否 在第二次酒精挑战期间，神经元激活钝化。如果他们 减少了，我们将检验以下假设。 下丘脑中CRF合成的降低，可能通过增加 对CRF神经元对糖皮质激素反馈的敏感性。并联 研究，我们还将使用慢性酒精治疗模型（B） 其中大鼠暴露于间歇性酒精蒸气2周，然后 一段时间长期的禁欲后，重新挑战了这种药物。 我们将首先确定B的动物是否也显示 重新暴露于酒精时，神经内分泌耐受性，或者是否为 在其他长期应力范式中观察到，它们将表现出 其HPA轴的响应加剧。无论哪种情况，机制 负责这些更改的负责。实验携带 另一方面，在特定的目标2下将使用敲除鼠 研究CRF及其受体对响应的重要性 HPA轴为酒精。在缺乏CRF的小鼠中，我们将检验假设 该CRF是这种反应的唯一中介。在纯合的小鼠中 Null CRF-R1等位基因，我们将测试垂体和/或 下丘脑CRF-R1参与酒精诱导的ACTH释放。最后 在CRF-R/2敲除小鼠中，我们将测试垂体的假设 和/或下丘脑CRF-R2对于此ACTH反应不需要。