The Effects of Neuroactive Steroids on Acute Ethanol Withdrawal in Mice

神经活性类固醇对小鼠急性乙醇戒断的影响

• 批准号: 7331657
• 负责人: Katherine R Kaufman
• 金额: $ 4.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2009-10-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331657
• 关键词: Acute; Adrenal Glands; Adrenalectomy; Alcohol withdrawal syndrome; Allopregnanolone; Aminobutyric Acid; Aminobutyric Acids; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Area; Behavior; Behavioral; Blood; Brain; Brain region; Cholesterol; Convulsants; DBA/2 Mouse; Data; Dose; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Ethanol; Excision; Female; Goals; Gonadal structure; Hippocampus (Brain); Hormones; Inbred Strain; Intoxication; Measurement; Mediating; Mus; Names; Neurons; Organ; Ovary; Pathway interactions; Peripheral; Physiological; Plasma; Pregnanes; Pregnanolone; Property; Radioimmunoassay; Research; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Role; Severities; Source; Steroids; Vertebral column; Withdrawal; alcohol effect; allotetrahydrodeoxycorticosterone; male; neuronal excitability; pregnane-20-one; receptor; response; sedative

DESCRIPTION (provided by applicant): Recent research has shown that some of ethanol's effects may be mediated by neuroactive steroid intermediaries. Neuroactive steroids increase in both brain and plasma in response to a modest dose of ethanol. These neuroactive steroids are able to potently modulate several receptors, most notable the K-aminobutyric acid type A receptors (GABAa). Modulation of GABAa receptors by neuroactive steroids such as allopregnanolone (ALLO, 3ohydroxy-5or-pregnan-20-one) has been shown to alter the antidepressant, anxiolytic, sedative and anti-convulsant properties of ethanol. The goal of this proposal is to elucidate the possible role of neurosteroids such as ALLO on acute ethanol withdrawal behaviors in C57BL/6 and DBA/2 mice, two inbred strains that differ markedly in acute ethanol withdrawal severity. Preliminary data has shown that removal of the peripheral sources of pregnane steroids (such as ALLO), primarily the adrenal glands in male mice and the adrenals and ovaries in females mice, increased acute ethanol withdrawal severity. The overall hypothesis is that adrenalectomy (ADX) and gonadectomy (GDX) significantly increase acute ethanol withdrawal by removing an inhibitory neuroactive steroid, such as ALLO. Studies related to Specific Aim 1 will determine which step along the neurosteroid pathway is necessary and/or sufficient to restore the withdrawal profile through systemic administration of neurosteroid precursors in the presence or absence of enzyme inhibitors after ADX and GDX. Once the specific biosynthetic step has been identified, studies related to Specific Aim 2 will microinject the neurosteroid or precursor into specific brain areas in animals that have the sources of neurosteroids removed through ADX and GDX and determine the effect on acute ethanol withdrawal. Concurrently, an analysis of GABAa receptor subunit expression (through RT-PCR) and measurements of hormone concentrations (through radioimmunoassay) will be undertaken in Specific Aim 3 to attempt to further understand the differences in withdrawal severity seen between two different inbred strains. This proposal will investigate the mechanism by which ethanol withdrawal causes rebound neuronal excitability in the hopes that elucidation of this mechanism will open avenues for treatment of ethanol withdrawal.

描述（由申请人提供）：最近的研究表明，某些乙醇的作用可能是由神经活性类固醇中介介导的。响应适量的乙醇，神经活性类固醇在大脑和血浆中增加。这些神经活性类固醇能够有效调节多个受体，最值得注意的是A型A型受体（GABAA）。通过神经活性类固醇（例如Allopregnanolone（Allo，3ohydroxy-5or-pregnan-20-one））对GABAA受体的调节已显示可改变乙醇的抗抑郁，抗焦虑，镇静和抗氧化剂的特性。该提案的目的是阐明神经类固醇（例如Allo）在C57BL/6和DBA/2小鼠中的急性乙醇戒断行为的可能作用，两种近交菌株在急性乙醇戒断严重程度方面显着不同。初步数据表明，去除妊娠类固醇（例如Allo）的外周来源，主要是雄性小鼠中的肾上腺以及雌性小鼠的肾上腺和卵巢，增加了急性乙醇戒断严重程度。总体假设是肾上腺切除术（ADX）和性腺切除术（GDX）通过去除抑制性神经活性类固醇（例如Allo）来显着增加急性乙醇的戒断。与特定目标1相关的研究将确定沿着神经素途径的哪个步骤和/或足以通过在ADX和GDX之后存在或不存在酶抑制剂的情况下通过系统地给予神经类固醇前体来恢复戒断谱。一旦确定了特定的生物合成步骤，与特定目标2相关的研究将对神经类固醇或前体进行微分记录到动物的特定大脑区域中，这些动物中具有通过ADX和GDX去除神经类固醇来源的动物，并确定对急性乙醇戒断的影响。同时，将在特定的目标3中对GABAA受体亚基表达（通过RT-PCR）进行分析（通过RT-PCR）和激素浓度的测量（通过放射免疫测定），以试图进一步了解两种不同的饲养菌株之间的戒断严重程度的差异。该提案将调查乙醇戒断引起反弹神经元兴奋性的机制，希望这种机制阐明该机制将开放以治疗乙醇戒断的途径。