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NIAAA资助的研究基础上，该研究表明，大气压力增加是乙醇的直接、机械性拮抗剂，可以阻断和逆转乙醇的广泛行为影响，以及乙醇对神经递质门控受体的作用，而不会导致行为或基线受体功能的变化。乙醇的这些压力拮抗特性为开发既能拮抗乙醇又不会引起不良反应的治疗剂提供了可能性。然而，我们并不认为压力本身就是治疗酒精中毒的一个可行的治疗工具。因此，本提案是将目前有关乙醇压力拮抗作用的知识转化为治疗酒精中毒的新型药物治疗药物的战略的第一步。这项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标的作用而不会导致受体正常功能或行为改变的药物。这项建议的主要目标是开始确定乙醇压力拮抗的分子机制和潜在的药理作用靶点。具体目的1.确定乙醇对甘氨酸、GABAA和GABAP受体的压力拮抗作用的分子部位。目的将分子方法与本实验室新近发展起来的高压双电极电压钳技术相结合，对非洲爪哇卵母细胞进行研究。第一阶段将测试压力通过作用于假定的乙醇的结合口袋而对抗乙醇的假设。第二阶段将测试压力通过作用于甘氨酸、GABAA和/或GABAP受体TM21TM3内的特定氨基酸或区域而拮抗乙醇的假设。具体目标2，将建立乙醇压力拮抗的部位(S)和机理(S)的分子模型。这一目标将使用我们的合作者开发的方法在LGICS中模拟乙醇的作用部位来实现。我们将使用来自Aim 1结果的数据来应用这一策略来模拟这些受体中的压力部位(S)和作用机制(S)。像Aim 2产生的那些模型将被用于未来的提案中，以设计能够模拟压力对介导酒精拮抗的分子靶标的作用的药理学药物。这些药物可以构成预防和治疗酒精中毒和酗酒的新策略的基础。

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.