Novel Mechanisms of Ethanol Potentiation of Rat Basolateral Amygdala GABA

乙醇增强大鼠基底外侧杏仁核 GABA 的新机制

• 批准号: 7559526
• 负责人: Yuval Silberman
• 金额: $ 1.46万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559526
• 关键词: Accounting; Acute; Agonist; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Bathing; Brain region; Breathing; Cells; Chemosensitization; Chromosome Pairing; Chronic; Comorbidity; Data; Distal; Emotional; Ethanol; Exposure to; Interneurons; Link; Mediating; Methods; Neon; Neuraxis; Norepinephrine; Norepinephrine Receptors; Physiologic pulse; Play; Population; Protocols documentation; Pulse taking; Rattus; Receptor Activation; Relapse; Research; Role; Site; Slice; Stress; Synapses; Synaptic Transmission; Thinking; Tissues; Traumatic Stress Disorders; Withdrawal; Work; alcohol exposure; base; biological adaptation to stress; drug of abuse; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; neurotransmission; noradrenergic; novel; patch clamp; postsynaptic; response; transmission process

DESCRIPTION (provided by applicant): Although alcohol (EtOH) is one of the oldest known drugs of abuse, the neuroliogical mechanisms underlying EtOH's actions are not fully known and as such, it remains difficult to understand how one may lose control of normal EtOH drinking resulting in alcoholism. Alcoholism is often found to be comorbid with anxiety and stress disorders, and while the eitology of this comorbidity is not fully known it has been proposed that since EtOH has long been known as an anxiolytic agent, some may imbibe as a way to selfmedicate their anxious or stressed states. Withdrawal from high EtOH levels has also been shown to result in an enhancement of anxious/stressed states, which may result in continued EtOH use and abuse. Therefore, it is hypothesized that EtOH may predominantly effect areas of the central nervous system (CMS) which mediate stress responses and anxiety, such as the basolateral amygdala (BLA). GABAergic synapses in the BLA have been shown to play a major role in emotional responses such as anxiety. Extensive research has shown that at least part of EtOH's effects in the CMS are due to an increase in GABAergic neurotransmission in numerous brain regions through both pre- and post-synaptic sites. Norepinephrine (NE), which is intimately linked to stress and anxiety disorders, has been shown increase GABA release in the BLA. Our preliminary data shows that NE receptor antagonists can block the potentiating effect of EtOH at a subset of GABAergic interneurons. Therefore it is hypothesized that EtOH enhances GABAergic transmission in the BLA in part via NE-receptor activity. The first specific aim is to determine the mechanisms by which acute EtOH enhances GABAergic neurotransmission at two subset of interneurons in the BLA. This aim will rely on whole-cell patch clamp electrophysiological methods to determine if the effects of bath application of EtOH on slices of BLA tissue are pre- and/or post-synaptic utilizing a combination of protocols focusing mainly on evoked inhibitory postsynaptic currents (IPSCs) spontaneous and miniature IPSCs and paired-pulses facilitation studies to isolate pre- and post-synaptic components of the EtOH enhancement of GABAergic neurotransmission. The second specific aim will determine the mechanism by which NE interacts with EtOH at BLA GABAergic synapse and which NE-receptor subtype mediates this effect. We will be using similar methods as described above as well as combinations of NE receptor agonists and antagonists to isolate the mechanism of the proposed NE-EtOH interaction in this brain region. The third specific aim will focus on the effects of chonic intermittent EtOH exposure via inhalation chamber exposure on subsequent acute EtOH exposure and the NE-EtOH interaction studied aims 1 and 2.

描述（由申请人提供）：虽然酒精 (EtOH) 是已知最古老的滥用药物之一，但 EtOH 作用的神经机制尚不完全清楚，因此，仍然很难理解人们如何失去对正常 EtOH 饮酒的控制，从而导致酒精中毒。酗酒经常被发现与焦虑和应激障碍共存，虽然这种共存疾病的病因尚不完全清楚，但有人提出，由于乙醇长期以来一直被认为是一种抗焦虑剂，因此一些人可能会将饮酒作为自我治疗焦虑或应激状态的一种方式。戒断高浓度乙醇也被证明会导致焦虑/压力状态加剧，这可能导致继续使用和滥用乙醇。 因此，推测乙醇可能主要影响中枢神经系统（CMS）介导应激反应和焦虑的区域，例如基底外侧杏仁核（BLA）。 BLA 中的 GABA 突触已被证明在焦虑等情绪反应中发挥着重要作用。广泛的研究表明，EtOH 对 CMS 的影响至少部分是由于通过突触前和突触后位点在许多大脑区域中 GABA 能神经传递增加所致。去甲肾上腺素 (NE) 与压力和焦虑症密切相关，已被证明会增加 BLA 中 GABA 的释放。我们的初步数据表明，NE 受体拮抗剂可以阻断 EtOH 对 GABA 能中间神经元子集的增强作用。因此，推测 EtOH 部分通过 NE 受体活性增强 BLA 中的 GABA 能传递。第一个具体目标是确定急性乙醇增强 BLA 中两个中间神经元亚群的 GABA 神经传递的机制。这一目标将依靠全细胞膜片钳电生理学方法来确定 EtOH 浴对 BLA 组织切片的影响是否是突触前和/或突触后，利用主要侧重于诱发抑制性突触后电流 (IPSC) 自发和微型 IPSC 以及成对脉冲促进研究来分离突触前和突触后的方案组合 EtOH 增强 GABA 能神经传递的成分。第二个具体目标将确定 NE 与 EtOH 在 BLA GABA 能突触处相互作用的机制以及哪种 NE 受体亚型介导这种效应。我们将使用与上述类似的方法以及 NE 受体激动剂和拮抗剂的组合来分离该大脑区域中所提出的 NE-EtOH 相互作用的机制。第三个具体目标将重点关注通过吸入室暴露的慢性间歇性乙醇暴露对随后的急性乙醇暴露的影响以及研究目标 1 和 2 的 NE-EtOH 相互作用。