Stress, alcohol and GABAergic neuroactive steroids in primates

描述（由申请人提供）：本提案的目的是探讨应激反应，饮酒和灵长类动物血浆中神经活性类固醇水平之间的关系。在啮齿动物模型中的大量证据表明，gaba能神经活性类固醇有助于乙醇敏感性、耐受性、防止依赖和减少过度饮酒。灵长类动物合成不同的类固醇前体，并表现出5preductase活性，因此需要开发一种高灵敏度的GCMS方法来测量灵长类动物血浆中孕酮、脱氧皮质酮和皮质醇的3< x5cc3和3a5p-降低代谢物。要测试的总体假设是，gaba能神经活性类固醇在灵长类动物的血浆中，在HPA轴激活和/或乙醇处理后升高，但在慢性乙醇暴露后下降。下丘脑垂体肾上腺轴的药理激活、酒精输注、诱导饮酒和慢性饮酒的影响将被研究，以确定对下丘脑垂体肾上腺轴挑战的神经活性类固醇反应与饮酒倾向之间是否存在关联。通过与小鼠和人类的类似研究进行比较，这些研究将被纳入INIA联盟。第一个目标是开发一种高灵敏度的GCMS方法来测量灵长类动物血浆中孕酮、脱氧皮质酮和皮质醇的3a5a-和3a5[3-减少代谢物。第二个目的是确定下丘脑（纳洛酮）、垂体（oCRF输注）或肾上腺（地塞米松预处理后ACTH输注）和全身乙醇给药水平的HPA轴刺激是否会改变猴子血浆中GAB A受体神经活性类固醇的水平。第三个目的是研究在使用相同的刺激程序刺激下丘脑轴后，计划性饮酒和即兴饮酒一年对前体类固醇和神经活性类固醇水平的影响。第四个目标将为其他INIA研究人员探索慢性乙醇暴露对小鼠、猕猴和酗酒者神经类固醇水平的影响提供服务核心。每位研究者将探索是否酒精或下丘脑轴刺激的神经活性类固醇反应被慢性酒精史改变或预测自愿饮酒水平。

DESCRIPTION (provided by applicant): The purpose of this proposal is to explore the relationship between stress response, alcohol drinking and neuroactive steroid levels in primate plasma. A large body of evidence in rodent models suggests that GABAergic neuroactive steroids contribute to ethanol sensitivity, tolerance, protection against dependence and reduces excessive alcohol consumption. Primates synthesize different steroid precursors and exhibit 5preductase activity that necessitates the development of a highly sensitive GCMS assay to measure both 3<x5ccand 3a5p- reduced metabolites of progesterone, deoxycorticosterone and cortisol in primate plasma. The overall hypothesis to be tested is that GABAergic neuroactive steroids are elevated in primate plasma following activation of the HPA axis and/or ethanol administration in ethanol nai've monkeys, but lost after chronic ethanol exposure. The effects of pharmacological activation of the hypothalamic pituitary adrenal axis, alcohol infusion, induction of alcohol drinking and chronic alcohol consumption will be investigated to determine if there is an association between neuroactive steroid responses to HPA axis challenge and the propensity to drink alcohol. These studies will be integrated into the INIA consortium by comparison with similar studies in mice and man. The first aim will develop a highly sensitive GCMS assay to measure both 3a5a- and 3a5[3- reduced metabolites of progesterone, deoxycorticosterone and cortisol in primate plasma. The second aim will determine if HPA axis stimulation at the level of the hypothalamus (naloxone administration), pituitary (oCRF infusion) or adrenal gland (ACTH infusion after dexamethasone pretreatment) and systemic ethanol administration alters the levels of GAB A receptor neuroactive steroids in plasma of monkeys. The third aim will investigate the effect of schedule-induced drinking and ad lib ethanol consumption for one year on both the precursor steroids and neuroactive steroid levels following HPA axis stimulation using the same challenge procedure. The fourth aim will provide a service core to other INIA investigators exploring the effects of chronic ethanol exposure on neurosteroid levels in mice, macaque monkeys and alcoholic humans. Each investigator will explore if neuroactive steroid responses to ethanol or HPA axis stimulation are altered by chronic ethanol history or predictive of voluntary alcohol consumption levels.