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: 7764811
• 负责人: A LESLIE MORROW
• 金额: $ 27.63万
• 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/7764811
• 关键词: Adrenal Glands; Alcohol consumption; Alcohol dependence; Alcohols; Biological Assay; Boutos; Chronic; Collaborations; Corticotropin; Corticotropin-Releasing Hormone; Data; Deoxycorticosterone; Dependence; Development; Dexamethasone; 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; 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; neurosteroids; 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）：该提案的目的是探索灵长类动物血浆中压力反应，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，免受依赖性的保护并减少过量的酒精消耗。灵长类动物合成了不同的类固醇前体和展示5个普罗脱脱酶活性，这使得必须开发高度敏感的GCMS测定法，以测量孕酮，脱氧皮质酮和皮质醇的3 <X5CCAND 3A5P降低的代谢物。要测试的总体假设是，在激活HPA轴和/或乙醇nai'monkeys的HPA轴和/或乙醇给药后，灵长类化的血浆中GABA能神经活性类固醇升高，但在慢性乙醇暴露后丢失。将研究下丘脑垂体肾上腺轴的药理激活，酒精输注，饮酒和慢性酒精消耗的影响，以确定神经活性类固醇对HPA轴对HPA轴挑战的反应与饮酒的倾向之间是否存在关联。通过与小鼠和人类的类似研究相比，这些研究将被整合到INIA联盟中。第一个目的将开发高度敏感的GCMS分析，以测量3A5A-和3A5 [3-降低孕酮，脱氧核酮和皮质醇的代谢产物中，在灵长类动物等离子体中。第二个目的将确定HPA轴在下丘脑水平（纳洛酮给药），垂体（OCRF输注）或肾上腺（去塞米松预处理后的ACTH输注）和全身性乙醇的刺激是否改变了GAB受体神经活性类固醇中的水平猴子。第三个目标将研究计划诱导的饮酒和AD LIB乙醇消耗一年对HPA轴刺激后使用相同挑战程序后的前体类固醇和神经活性类固醇水平的影响。第四目标将为其他INIA调查人员提供服务核心，以探索慢性乙醇暴露对小鼠，猕猴和酒精人类的神经类固醇水平的影响。每个研究者将探索神经活性类固醇对乙醇或HPA轴刺激的反应是否会因慢性乙醇史而改变或预测自愿性饮酒水平。