SYNAPTIC AMINO ACID TRANSPORT: ALCOHOL AND ALCOHOLISM

突触氨基酸运输：酒精和酗酒

• 批准号: 3111803
• 负责人: DENNIS E RHOADS
• 金额: $ 8.41万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3111803
• 关键词: GABA receptor; adenosinetriphosphatase; alcoholic beverage consumption; alcoholism /alcohol abuse; aminoacid transport; drug adverse effect; drug metabolism; drug withdrawal; gamma aminobutyrate; gel electrophoresis; ion exchange chromatography; membrane activity; neural transmission; potassium channel; scintillation counter; scintillation spectrometry; sodium channel; synapses; tissue /cell culture; ultracentrifugation; ultraviolet spectrometry

Toward unifying hypotheses for the cause of alcohol-associated disease, major efforts have centered on: (1) metabolic changes associated with ethanol catabolism, and (2) physical disordering of cellular membranes by ethanol with resulting alterations in membrane function. This proposal focuses on the latter or "membrane hypothesis" of alcohol action to study both acute and chronic effects of ethanol on synaptic membrane function in the central nervous system (CNS). Ethanol is among the mostly commonly abused psychotropic drugs and abstinence after chronic use leads to withdrawal symptoms that constitute physical dependence. Altered neural activity associated with gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, and the postsynaptic GABA/benzodiazepine receptor complex has been implicated in both acute and chronic effects of ethanol in the CNS. Isolated nerve ending preparations (synaptosomes) from adult rat brain will be employed to study presynaptic effects of ethanol on the GABA transport system. Rats will be fed normal rat chow or liquid diets containing alcohol or isocaloric carbohydrate to determine acute and chronic effects of ethanol on this transport system which controls the steady-state and dynamic concentrations of GABA in the synapse. Evidence is presented that ethanol can potentiate or inhibit GABAergic activity by dose-dependent alterations in this presynaptic system. Mechanisms to be investigated involve several interacting membrane components including the GABA transport protein, Na+, K+-ATPase (the driving force for the transport), ATPase-modulating peptide(s), and the lipids surrounding these components in the synaptic membrane. Of particular interest is the observation that the presence or absence of an easily extractable protein(s) defines whether ethanol is stimulatory or inhibitory (in the physiological concentration range) to the Na+, K+-ATPase and, thereby, to transport of GABA. The amount and disposition of such an "ethanol-modifying factor" in the membrane could be a genetically- determined component accounting for individual variability in response to alcohol use/abuse. Such studies are needed to elucidate neurochemical bases for alcohol intoxication and dependence. This will both promote understanding of the associated-diseases and identify critical functional components of synaptic membranes that are altered by ethanol use/abuse and to which treatment might be directed.

统一假设与酒精相关疾病的原因， 重大努力集中在：（1）与 乙醇分解代谢和（2）通过 乙醇，导致膜功能的改变。 这个建议 侧重于酒精作用的后者或“膜假说” 乙醇对突触膜功能的急性和慢性作用在 中枢神经系统（CNS）。 乙醇是最常见的 长期使用后滥用精神药物和禁欲导致 构成身体依赖的戒断症状。 与γ-氨基丁酸（GABA）相关的神经活性改变了 大脑中的主要抑制性神经递质和突触后 GABA/苯二氮卓受体复合物已与急性和 乙醇在中枢神经系统中的慢性作用。 孤立的神经结束准备 （突触体）将使用成年大鼠大脑进行突触前研究 乙醇对GABA运输系统的影响。 大鼠会被喂养正常 大鼠食物或含有酒精或等热碳水化合物的液体饮食 确定乙醇对该传输系统的急性和慢性影响 它控制着GABA的稳态和动态浓度 突触。 有证据表明乙醇可以增强或抑制 在这种突触前的剂量依赖性改变通过剂量依赖性的GABA能活性 系统。 要研究的机制涉及几种相互作用的膜 包括GABA转运蛋白的组件，Na+，K+-ATPase（The 运输的驱动力），ATPase调节肽（S）和 突触膜中这些成分周围的脂质。 的 特别感兴趣的是观察到存在或不存在 易于提取的蛋白质定义乙醇是刺激性还是 抑制性（在生理浓度范围内）Na+，K+-ATPase 然后，加巴运输。 这样的金额和处置 膜上的“乙醇修饰因子”可能是遗传上的 确定的组件核算个人可变性，以响应个人可变性 酒精使用/滥用。 需要进行此类研究来阐明神经化学 酒精中毒和依赖性基础。 这两个都会促进 理解相关的脉冲并确定关键功能 因乙醇使用/滥用而改变的突触膜的组成部分 可以指导治疗的方法。