NEUROSTEROIDS AND ETHANOL INTERACTIONS

神经类固醇和乙醇的相互作用

• 批准号: 7218045
• 负责人: A LESLIE MORROW
• 金额: $ 26.64万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218045
• 关键词: Abnormal coordination; Accounting; Acute; Address; Adrenal Medulla; Adrenalectomy; Alcohol consumption; Alcoholism; Alcohols; Allopregnanolone; Anabolism; Anti-Anxiety Agents; Anticonvulsants; Astrocytes; Attenuated; Behavioral; Brain; Cerebral cortex; Cerebrum; Chemosensitization; Consumption; Development; Dose; Elevation; Enzymes; Ethanol; Ethanol dependence; Etiology; Fire - disasters; Genomics; Goals; HPSE gene; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Injection of therapeutic agent; Intoxication; Investigation; Knock-out; Knockout Mice; Knowledge; Lead; Maize; Measures; Mediating; Medulla of ovary; Metabolism; Monkeys; Motor; Mutant Strains Mice; Neuroglia; Neurons; Numbers; Oxidoreductase; Peripheral; Physiological; Plasma; Play; Pregnanes; Progesterone; Purpose; Rate; Rattus; Reflex action; Research; Research Personnel; Role; Seizures; Sleep; Steroid biosynthesis; Steroids; Testing; Time; Tissues; Training; Zea mays; alcohol abuse therapy; alcohol effect; chromosome 5q loss; chronic alcohol ingestion; drug discrimination; hypothalamic-pituitary-adrenal axis; in vivo; inhibitor/antagonist; male; neurochemistry; neurophysiology; neurotransmission; novel; pregnane-20-one; prevent; programs; receptor; receptor function; relating to nervous system; response; stressor; toe corn

The objective of this proposal is to explore the potential role of endogenous 3a-hydroxy-5a-pregnan-20-one (3a,5a-THP) in the electrophysiological and behavioral actions of ethanol, including the development of ethanpl tolerance. We recently discovered that ethanol administration to rats produces an elevation in plasma and brain levels of the potent GABAA receptor neuroactive steroid. 3a,5a-THP. to pharmacologically relevant concentrations. The effects of ethanol on 3a,5a-THP levels in cerebral cortex are time and dose dependent and sufficient to potentiate GABAA receptor function. Moreover, there is a strong correlation between ethanol sleep time and cerebral cortical levels of 3a.5a-THP. In contrast, brain levels of 3a,5a-THP are not altered by acute ethanol challenge in ethanol dependent rats, therefore, tolerance may develop to the effect of ethanol on the induction of 3a,5a-THP. The loss of ethanol induction of 3a,5a-THP levels may underlie tolerance to the pharmacological effects of ethanol. Therefore, we propose to test the overall hypothesis that 3a,5cc-THP mediates pharmacological effects of ethanol in vivo. The first goal is to investigate the role of 3a,5a-THP in the behavioral and neurophysiological effects of ethanol. 3a,5cc-THP formation will be prevented by pretreatment steroid biosynthesis inhibitors and the effects of ethanol on neuronal firing rates, GABAA receptor-mediated inhibition of spontaneous neuronal activity, intoxication, aerial righting reflex and seizure thresholds will be measured. The role of 3a,5a-THP will also be investigated in conditional knock-out mice that lack 3a-hydroxysteroid dehydrogenase - the final step in 3a,5a- THP formation. The second aim will determine if 3a,5oc-THP plays a role in the development of tolerance to ethanol using both knock out mice and steroid biosynthesis inhibitors. The third aim will focus on the mechanisms of 3a,5cc-THP accumulation following ethanol administration. Studies will be conducted to determine if ethanol directly alters the activity of the 3a,5cc-THP biosynthetic enzymes. Preliminary results suggest that ethanol may increase 3a,5a-THP biosynthesis, while high dose ethanol may release or uncover a "store" of 3a,5oc-THP. The effect of ethanol on 3oc,5a-THP release from cultured astrocytes will be measured. These studies will address the effects of ethanol at rapid time points (seconds to minutes) that may be relevant to the electrophysiological actions of ethanol. These studies may elucidate a new mechanism of ethanol action in the CNS and explain why the effects of ethanol on GABAergic neurotransmission could not be adequately explained by the direct action of ethanol at GABA.4 receptors. The results of this investigation will extend our knowledge of the potential role of neurosteroids in ethanol action and ethanol tolerance and may identify new factors involved in the etiology of alcoholism.

该提案的目的是探索内源性 3a-羟基-5a-pregnan-20-one 的潜在作用 (3a,5a-THP) 在乙醇的电生理和行为作用中的作用，包括乙醇的发展 宽容。我们最近发现，给老鼠注射乙醇会导致血浆和大脑的升高 有效的 GABAA 受体神经活性类固醇的水平。 3a,5a-THP。与药理学相关 浓度。乙醇对大脑皮层 3a,5a-THP 水平的影响具有时间和剂量依赖性，并且 足以增强 GABAA 受体功能。此外，乙醇睡眠与睡眠之间存在很强的相关性。 时间和 3a.5a-THP 的大脑皮质水平。相比之下，急性应激反应不会改变大脑中 3a,5a-THP 的水平。 乙醇依赖性大鼠的乙醇挑战，因此，耐受性可能会发展为乙醇对乙醇的影响 3a,5a-THP 的诱导。乙醇诱导的 3a,5a-THP 水平的丧失可能是对 乙醇的药理作用。因此，我们建议检验 3a,5cc-THP 的总体假设 介导乙醇在体内的药理作用。 第一个目标是研究 3a,5a-THP 在行为和神经生理学效应中的作用 乙醇。预处理类固醇生物合成抑制剂将阻止 3a,5cc-THP 的形成，并且 乙醇对神经元放电率的影响，GABAA 受体介导的自发神经元活动的抑制， 将测量中毒、空中翻正反射和癫痫阈值。 3a,5a-THP 的作用也将是 在缺乏 3a-羟基类固醇脱氢酶（3a,5a- 的最后一步）的条件敲除小鼠中进行了研究 THP 形成。第二个目标将确定 3a,5oc-THP 是否在耐受性的发展中发挥作用 使用基因敲除小鼠和类固醇生物合成抑制剂来产生乙醇。第三个目标将侧重于机制 乙醇施用后 3a,5cc-THP 的积累。将进行研究以确定乙醇是否 直接改变 3a,5cc-THP 生物合成酶的活性。初步结果表明乙醇可能 增加 3a,5a-THP 生物合成，而高剂量乙醇可能会释放或揭示 3a,5oc-THP 的“储存”。这 将测量乙醇对培养的星形胶质细胞释放 3oc,5a-THP 的影响。这些研究将解决 乙醇在快速时间点（秒到分钟）的影响可能与电生理作用相关 乙醇。这些研究可能阐明乙醇在中枢神经系统中作用的新机制，并解释其影响的原因 乙醇对 GABA 能神经传递的影响不能用乙醇对 GABA 能神经传递的直接作用来充分解释。 GABA.4 受体。这项研究的结果将扩展我们对神经类固醇潜在作用的认识 乙醇作用和乙醇耐受性，并可能确定酒精中毒病因学中涉及的新因素。