EFFECTS OF ALCOHOL ON CENTRAL NEUROENDOCRINE SYSTEMS

我们最近观察到，暴露在酒精中的老鼠 通过留置胃内插管（模型A）连续几天显示， 预期血浆ACTH和皮质酮水平的初始升高，但 在3-12天后用药物再次激发时，这些激素反应 明显变钝了在具体目标1下，我们将检验假设 相关的机制，负责减少HPA轴在这一点上， 短期酒精治疗模式。我们将首先确定 垂体对CRF和/或加压素的反应性降低。如果这是 在这种情况下，我们将测试的假设，稳态mRNA水平的 垂体CRF-R1和/或POMC降低，和/或垂体 对糖皮质激素反馈更敏感使用转录水平的 立即早期基因NGFI-B，我们还将确定下丘脑是否 神经元活化在第二次酒精刺激期间减弱。如果他们 减少，我们将测试的假设，这是伴随着 下丘脑中CRF合成减少，可能通过增加 CRF神经元对糖皮质激素反馈的敏感性。并行 研究中，我们还将使用慢性酒精治疗模型（模型B）， 其中大鼠暴露于间歇性酒精蒸汽2周，然后 在长期禁欲后再次使用该药物。 我们将首先确定模型B的动物是否也表现出 神经内分泌耐受性，当再次暴露于酒精或是否，作为 与其他长期压力模式观察，他们将表现出一个 他们的HPA轴的反应加剧。无论哪种情况， 将对这些变化进行调查。实验一式 另一方面，在特定目标2下，将使用基因敲除小鼠， 研究CRF及其受体对反应的重要性， HPA轴与酒精有关。在CRF缺陷小鼠中，我们将检验这一假设 CRF是这种反应的唯一媒介。在a基因纯合子小鼠中 无效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ACTH释放。最后 在CRF-R/2基因敲除小鼠中，我们将检验垂体 和/或下丘脑CRF-R2对于这种ACTH应答不是必需的。

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.