Pressure-Based Pharmacological Alcoholism Treatments

描述（由申请人提供）： 目前的探索性R21拨款提案建立在我们的NIAAA资助的研究基础上，表明大气压力增加是乙醇的直接，机械拮抗剂，可以阻断和逆转乙醇的广泛行为效应，以及乙醇对神经递质门控受体的作用，而不会引起行为或基线受体功能的变化。乙醇的这些压力拮抗性质提供了开发拮抗乙醇而不引起不良反应的治疗剂的可能性。然而，我们并不认为压力本身是治疗酗酒的可行的治疗工具。因此，本提案代表了将关于乙醇的压力拮抗作用的现有知识转化为用于治疗酒精中毒的新型药物制剂的策略的第一步。拟议工作的长期目标是开发模拟压力并拮抗乙醇对受体内分子靶点的作用而不引起受体或行为正常功能变化的药理学试剂。该提案的主要目标是开始确定乙醇压力拮抗作用的分子机制和药理学试剂的潜在靶点。具体目标1。确定甘氨酸、GABAA和GABAP受体中乙醇压力拮抗作用的分子位点。目的将分子生物学方法与高压双电极电压钳技术相结合，对非洲爪蟾卵母细胞进行研究。第一阶段将测试压力通过作用于假定的乙醇结合口袋来对抗乙醇的假设。“第二阶段将测试压力通过作用于甘氨酸、GABAA和/或GABAP受体的TM 21 TM 3内的特定氨基酸或区域来拮抗乙醇的假设。具体目标2，将开发乙醇压力拮抗作用位点和机制的分子模型。这一目标将通过我们的合作者开发的方法来实现，以模拟乙醇在LGICS中的作用位点。我们将使用目标1结果的数据应用该策略来模拟这些受体中的压力部位和作用机制。像那些从目标2中产生的模型将用于未来的建议，以设计药理学药物，可以模拟压力对介导酒精拮抗作用的分子靶点的作用。这些药物可以成为酒精中毒和酒精滥用的新型预防和治疗策略的基础。

DESCRIPTION (provided by applicant): The present exploratory R21 grant proposal builds on our NIAAA funded research showing that increased atmospheric pressure is a direct, mechanistic antagonist for ethanol that blocks and reverses a broad spectrum of ethanol's behavioral effects, and ethanol's action on neurotransmitter-gated receptors, without causing changes in behavior or baseline receptor function. These qualities of pressure antagonism of ethanol hold out the possibility of developing therapeutic agents that antagonize ethanol without causing adverse effects. However, we do not feel that pressure per se represents a viable therapeutic tool for treating alcoholism. Therefore, the present proposal represents the first step in a strategy for translating current knowledge regarding pressure antagonism of ethanol to the development of novel pharmacotherapeutic agents for treating alcoholism. The long-term goal of the proposed work is to develop pharmacological agents that mimic pressure and antagonize ethanol's action on molecular targets within receptors without causing changes in normal function of the receptors or behavior. The primary goal of this proposal is to begin to determine the molecular mechanism of pressure antagonism of ethanol and potential targets for pharmacological agents. Specific Aim 1. Identify the molecular sites of action of pressure antagonism of ethanol in glycine, GABAA and GABAP receptors. Aim I will be accomplished by combining molecular approaches with hyperbaric two-electrode voltage clamp techniques in Xenopus oocytes recently developed by our laboratory. Phase I will test the hypothesis that pressure antagonizes ethanol by acting on putative ethanol 'binding pockets." Phase 2 will test the hypothesis that pressure antagonizes ethanol by acting on specific amino acids or regions within TM21TM3 of glycine, GABAA and/or GABAP receptors. Specific Aim 2, will develop molecular models for the site(s) and mechanism(s) of pressure antagonism of ethanol. This aim will be accomplished using methods developed by our collaborators to model ethanol's sites of action in LGICS. We will apply this strategy using data from Aim 1 results to model pressures site(s) and mechanism(s) of action in these receptors. Models like those to be generated from Aim 2 will be used in future proposals to design pharmacological agents that can mimic pressure's action on molecular targets mediating alcohol antagonism. These agents can form the bases of novel prevention and treatment strategies for alcoholism and alcohol abuse.