Stress, alcohol and GABAergic neuroactive steroids in primates

灵长类动物的压力、酒精和 GABA 神经活性类固醇

• 批准号: 7215952
• 负责人: A LESLIE MORROW
• 金额: $ 25.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215952
• 关键词: Adrenal Glands; Alcohol consumption; Alcohol dependence; Alcohols; Biological Assay; Boutos; Chronic; Collaborations; Corticotropin; Corticotropin-Releasing Hormone; Data; Deoxycorticosterone; Dependence; Development; Dexamethasone; Elevation; Endocrine; Ethanol; Exhibits; GABA Agonists; Grant; Heavy Drinking; Home environment; Hormones; Human; Hydrocortisone; Hypothalamic structure; Individual; Individual Differences; Infusion procedures; Link; Macaca; Macaca fascicularis; Macaca mulatta; Mass Fragmentography; Measures; Monkeys; Mus; Naloxone; Oxidoreductase; Pituitary Gland; Plasma; Primates; Procedures; Progesterone; Purpose; Recording of previous events; Research Personnel; Rodent Model; Role; Sampling; Schedule; Seizures; Services; Social Dominance; Steroids; Stress; Testing; Water; Withdrawal; Work; alcohol exposure; alcohol response; alcohol sensitivity; biological adaptation to stress; chronic alcohol ingestion; drinking; hypothalamic-pituitary-adrenal axis; man; novel; problem drinker; programs; receptor; response; trait

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.

描述（由申请人提供）：本提案的目的是探讨灵长类动物血浆中应激反应、饮酒和神经活性类固醇水平之间的关系。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、防止依赖并减少过量饮酒。灵长类动物合成不同的类固醇前体并表现出5-还原酶活性，因此需要开发高度灵敏的GCMS测定法来测量灵长类动物血浆中黄体酮、脱氧皮质酮和皮质醇的3<x5cc和3a5p-还原代谢物。待测试的总体假设是，在未接触过乙醇的猴子中，HPA 轴激活和/或乙醇施用后，灵长类动物血浆中的 GABA 能神经活性类固醇升高，但在长期接触乙醇后消失。将研究下丘脑垂体肾上腺轴的药物激活、酒精输注、诱导饮酒和长期饮酒的影响，以确定神经活性类固醇对 HPA 轴挑战的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度灵敏的 GCMS 测定法，以测量灵长类动物血浆中黄体酮、脱氧皮质酮和皮质醇的 3a5a- 和 3a5[3- 还原代谢物。第二个目标将确定下丘脑（纳洛酮给药）、垂体（oCRF 输注）或肾上腺（地塞米松预处理后输注 ACTH）水平的 HPA 轴刺激以及全身乙醇给药是否会改变血浆中 GABA 受体神经活性类固醇的水平猴子。第三个目标将研究使用相同的激发程序刺激 HPA 轴后，计划诱导的饮酒和随意乙醇消耗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 研究人员提供服务核心，探索慢性乙醇暴露对小鼠、猕猴和酗酒人类神经类固醇水平的影响。每位研究者将探讨慢性乙醇史或自愿饮酒水平的预测是否会改变神经活性类固醇对乙醇或 HPA 轴刺激的反应。