Alcohol and mesolimbic glutamatergic transmissions

酒精和中脑边缘谷氨酸能传递

• 批准号: 7586252
• 负责人: JIANG-HONG YE
• 金额: $ 34.84万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586252
• 关键词: AMPA Receptors; Acute; Agonist; Alcohol dependence; Alcoholism; Alcohols; Area; Attenuated; Axon; Brain; Cells; Collaborations; DRD2 gene; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dopamine Uptake Inhibitors; Dopaminergic Cell; Electrophysiology (science); Ethanol; Excitatory Amino Acid Antagonists; Excitatory Synapse; Figs - dietary; Frequencies; Glutamates; Goals; Health; Interneurons; Link; Literature; Measurement; Mediating; Midbrain structure; Molecular; Molecular Genetics; Mus; N-Methyl-D-Aspartate Receptors; Nucleus Accumbens; Olives - dietary; Output; Pathway interactions; Pharmacology; Physiologic pulse; Play; Prefrontal Cortex; Preparation; Principal Investigator; Process; Rattus; Receptor Signaling; Reserpine; Rewards; Role; Scheme; Slice; Source; Synapses; Synaptic Transmission; Techniques; Testing; United States; Ventral Tegmental Area; Work; addiction; alcohol effect; alcoholism prevention; base; clinically relevant; depressed; dopaminergic neuron; effective therapy; extracellular; immunocytochemistry; improved; in vivo; innovation; interdisciplinary approach; neurochemistry; novel; postsynaptic; presynaptic; prevent; programs; public health relevance; reuptake; transmission process

DESCRIPTION (provided by applicant): Alcoholism in the United States is a serious health concern. Our long-term goal is to elucidate the mechanisms underlying alcohol addiction, a necessary prerequisite to the development of effective therapy. The specific hypothesis is that acute ethanol increases glutamate release via activation of dopamine D1 receptors (D1R). The increased glutamatergic transmission in turn modulates dopaminergic cell activity in the reward pathway and thus plays a significant role in the processes involved in alcohol addiction. We base this hypothesis on the following observations: a) clinically relevant concentrations of ethanol (10-80 mM) increase the amplitude of evoked excitatory postsynaptic currents (EPSCs) mediated by AMPA receptors. In addition, ethanol reduces paired-pulse facilitation of evoked EPSCs and increased the frequency but not the amplitude of spontaneous EPSCs. Furthermore, ethanol increases extracellular glutamate levels in the ventral tegmental area (VTA) in midbrain slices and in vivo in rats; and b) the effects of ethanol are mimicked by a D1R agonist or a dopamine reuptake inhibitor, and they are blocked by a D1R antagonist or by depleting dopamine stores with reserpine. This hypothesis will be tested in the VTA of rats or mice by a combination of electrophysiological and pharmacological techniques. This includes measurements of extracellular glutamate and dopamine levels in both the VTA and the nucleus accumbens, in brain slices and/or in vivo. The Specific Aims are to determine: 1) The effects of ethanol on glutamatergic transmission to VTA dopamine neurons. We will compare AMPA receptor-mediated EPSCs and extracellular glutamate and dopamine levels in the absence and presence of ethanol. 2) The role of presynaptic D1Rs in the ethanol-induced increase in glutamatergic transmission to VTA dopamine neurons. We will compare the effects of ethanol on EPSCs and on extracellular glutamate levels in the absence and presence of a D1R agonist or antagonist. 3) The functional consequences of ethanol-mediated facilitation of glutamate release on the output of VTA dopamine neurons. We will determine whether glutamate antagonists: 1) attenuate the effects of ethanol on the excitability of VTA DA neurons, and 2) block the ability of systemic ethanol to increase dopamine release in the nucleus accumbens when the antagonists are infused into the VTA. PUBLIC HEALTH RELEVANCE The results of these studies will clarify a novel mechanism that is a significant component of the action of ethanol on the brain`s reward pathways. A better understanding of cellular mechanisms of alcohol addiction will improve the treatment and prevention of alcoholism.

描述（由申请人提供）：在美国，酗酒是一个严重的健康问题。我们的长期目标是阐明酒精成瘾的机制，这是开发有效疗法的必要先决条件。具体假设是，急性乙醇通过激活多巴胺 D1 受体 (D1R) 增加谷氨酸释放。增加的谷氨酸传递反过来调节奖赏途径中的多巴胺能细胞活性，从而在酒精成瘾的过程中发挥重要作用。我们的假设基于以下观察结果：a) 临床相关浓度的乙醇 (10-80 mM) 会增加由 AMPA 受体介导的诱发兴奋性突触后电流 (EPSC) 的幅度。此外，乙醇减少了诱发 EPSC 的配对脉冲促进，并增加了自发 EPSC 的频率，但没有增加其幅度。此外，乙醇会增加中脑切片和大鼠体内腹侧被盖区（VTA）的细胞外谷氨酸水平。 b) D1R 激动剂或多巴胺再摄取抑制剂可模拟乙醇的作用，并且可被 D1R 拮抗剂或利血平耗尽多巴胺储备来阻断。该假设将通过电生理学和药理学技术的结合在大鼠或小鼠的 VTA 中进行测试。这包括在脑切片和/或体内测量 VTA 和伏核中的细胞外谷氨酸和多巴胺水平。具体目标是确定： 1) 乙醇对谷氨酸能传递至 VTA 多巴胺神经元的影响。我们将比较在不存在和存在乙醇的情况下 AMPA 受体介导的 EPSC 以及细胞外谷氨酸和多巴胺水平。 2)突触前D1R在乙醇诱导的VTA多巴胺神经元谷氨酸传递增加中的作用。我们将比较在不存在和存在 D1R 激动剂或拮抗剂的情况下乙醇对 EPSC 和细胞外谷氨酸水平的影响。 3）乙醇介导的谷氨酸释放促进对VTA多巴胺神经元输出的功能影响。我们将确定谷氨酸拮抗剂是否：1）减弱乙醇对 VTA DA 神经元兴奋性的影响，2）当拮抗剂注入 VTA 时，阻断全身乙醇增加伏核中多巴胺释放的能力。公共卫生相关性这些研究的结果将阐明一种新机制，该机制是乙醇对大脑奖赏通路作用的重要组成部分。更好地了解酒精成瘾的细胞机制将改善酒精中毒的治疗和预防。