NEUROSTEROIDS AND ETHANOL INTERACTIONS

神经类固醇和乙醇的相互作用

基本信息

批准号：
7599239
负责人：
A LESLIE MORROW
金额：
$ 30.52万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7599239
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 Enzymes Ethanol Ethanol dependence Etiology Genomics Goals Human Hydrocortisone Hydroxysteroid Dehydrogenases Injection of therapeutic agent Intoxication Investigation Knock-out Knockout Mice Knowledge Lead Measures Mediating Medulla of ovary Metabolism Monkeys Motor Mutant Strains Mice Neuroglia Neurons Oxidoreductase Peripheral Physiological Plasma Play Pregnanes Progesterone Rattus Reflex action Research Research Personnel Role Seizures Sleep Steroid biosynthesis Testing Time Tissues Training alcohol effect alcoholism therapy chromosome 5q loss chronic alcohol ingestion drug discrimination in vivo inhibitor/antagonist male neurochemistry neurophysiology neurosteroids neurotransmission novel pregnane-20-one prevent programs receptor receptor function relating to nervous system response stressor

项目摘要

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.

该提议的目的是探索内源性3A-Hydroxy-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，包括乙醇的发展宽容。我们最近发现，对大鼠的乙醇给药会产生血浆和大脑的升高有效的GABAA受体神经活性类固醇水平。 3a，5a-thp。与药理学相关浓度。乙醇对脑皮质中3A，5A-THP水平的影响是时间和剂量依赖性，并且足以增强GABAA受体功能。而且，乙醇睡眠之间存在很强的相关性时间和脑皮质水平为3a.5a-thp。相比之下，急性不会改变3A的大脑水平，5a-thp不会改变因此，乙醇依赖性大鼠的乙醇挑战可能会发展到乙醇对乙醇的影响诱导3a，5a-thp。 3A乙醇诱导的丧失，5a-thp水平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在行为和神经生理影响中的作用乙醇。 3A，5CC-THP的形成将通过预处理类固醇生物合成抑制剂和乙醇对神经元的发射速率，GABAA受体介导的自发神经元活性的抑制作用，中毒，将测量空中右反射和癫痫发作阈值。 3a，5a-thp的作用也将是在有条件缺乏3A-羟基固醇脱氢酶的条件敲除小鼠中进行了研究 - 3A，5A-的最后一步 THP形成。第二个目标将确定3a，5oc-thp是否在耐受性的发展中起作用乙醇都使用小鼠和类固醇生物合成抑制剂。第三个目标将重点放在机制上乙醇给药后的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“存储”。这将测量乙醇对3OC，5A-THP释放从培养的星形胶质细胞中释放的影响。这些研究将解决乙醇在快速时间点（秒至分钟）的影响，可能与电生理作用有关乙醇。这些研究可以阐明中枢神经系统中乙醇作用的新机制，并解释为什么影响乙醇在GABA能神经传递上的乙醇的直接作用无法充分说明 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了解在乙醇作用和乙醇耐受性中，可以确定酗酒病因涉及的新因素。