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: 7330054
• 负责人: Yuval Silberman
• 金额: $ 4.1万
• 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 2009-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7330054
• 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）：尽管酒精（ETOH）是已知的最古老的滥用药物之一，但ETOH作用的神经素质学机制尚不完全了解，因此，很难理解如何失去对正常饮酒的控制，从而导致酒精中毒。酒精中毒通常被发现与焦虑和压力障碍合并，尽管这种合并症的生物学尚不完全众所周知，但已提出，由于EtoH长期以来一直被称为抗焦虑药，但有些人可能会吸收自己的焦虑或压力状态。还显示从高ETOH水平退出会导致焦虑/压力状态的增强，这可能导致ETOH的持续使用和滥用。 因此，假设ETOH可能主要影响中枢神经系统（CMS）介导压力反应和焦虑的区域，例如基底外侧杏仁核（BLA）。 BLA中的GABA能突触已被证明在诸如焦虑之类的情绪反应中起着重要作用。广泛的研究表明，ETOH在CMS中的至少部分效应是由于通过突触前和突触后的许多大脑区域中GABA能神经传递的增加所致。与压力和焦虑症密切相关的去甲肾上腺素（NE）已显示出BLA中的GABA释放增加。我们的初步数据表明，NE受体拮抗剂可以阻止EtOH在GABA能中间神经元子集中的增强作用。因此，假设ETOH可以通过NE受体活性部分增强BLA的GABA能传播。第一个具体目的是确定急性ETOH在BLA中两个子集中增强GABA能神经传递的机制。 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 GABA能神经传递的ETOH增强的组成部分。第二个特定目的将确定NE在BLA GABA能突触中与ETOH相互作用的机制，哪些NE受体亚型介导了这种作用。我们将使用如上所述的类似方法以及NE受体激动剂和拮抗剂的组合来隔离该大脑区域所提出的NE-ETOH相互作用的机制。第三个具体目的将集中于通过吸入室暴露对随后的急性ETOH暴露和研究的NE-ETOH相互作用AIM 1和2的影响。