ETHANOL, NEUROSTEROIDS & HIPPOCAMPAL PLASTICITY

乙醇、神经类固醇

• 批准号: 8299168
• 负责人: CHARLES F ZORUMSKI
• 金额: $ 36.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299168
• 关键词: Acute; Adverse drug effect; Adverse effects; Alcohol abuse; Alcoholic Intoxication; Alcohols; Aminobutyric Acids; Ataxia; Behavioral; Behavioral Symptoms; Cessation of life; Chronic; Cognition; Communication; Complex; Dementia; Ethanol; Euphoria; Exhibits; Exposure to; Generations; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); Hour; Individual; Intoxication; Laboratories; Life; Long-Term Depression; Long-Term Effects; Long-Term Potentiation; Mediating; Memory; Mental Depression; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Nervous system structure; Neurobehavioral Manifestations; Neurons; Pharmaceutical Preparations; Process; Production; Rattus; Reaction Time; Risk Factors; Role; Sedation procedure; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; United States; Ventilatory Depression; alcohol abuse therapy; alcohol effect; alcohol exposure; binge drinking; cognitive function; drug of abuse; gamma-Aminobutyric Acid; ifenprodil; memory process; neurosteroids; novel; prevent; receptor; research study; synaptic function; synaptic inhibition; transmission process

DESCRIPTION (provided by applicant): Acute ethanol intoxication is associated with behavioral and cognitive symptoms that include problems with memory processing. In some cases, ethanol intoxication can result in a complete inability to process new information, a condition known as a "blackout". Understanding how ethanol alters cognition and memory is important for determining ways to protect the nervous system from the short- and long-term adverse effects of the drug. Although the mechanisms underlying memory processing in the mammalian nervous system are not completely understood, present evidence suggests that use-dependent forms of synaptic plasticity at glutamate synapses in the hippocampus, including long-term potentiation (LTP) and long-term depression (LTD), are relevant. For the past several years our laboratory has examined the acute effects of ethanol on synaptic transmission and synaptic plasticity in the CA1 region of rat hippocampal slices. We have found that ethanol acutely inhibits a specific subtype of synaptic N-methyl-D-aspartate receptor (NMDAR) that is also inhibited by the NR1/NR2B antagonist, ifenprodil. Block of LTD by ethanol correlates with the block of these synaptic NMDARs. Effects on LTP are more complex and persistent, and involve effects on gamma-aminobutyric acid (GABA)-mediated inhibitory transmission. In recent studies, we found that GABA-enhancing neurosteroids contribute to the ability of ethanol to block LTpreliminary Additionally, the ability of ethanol to block LTP depends upon how ethanol is administered, with acute applications of high concentrations blocking LTP and slower step-wise increases in ethanol concentration to high levels resulting in a form of acute tolerance. In this project, we will extend these initial observations and pursue three sets of studies that will examine: 1. How GABAergic neurosteroids contribute to acute effects of ethanol on LTP; 2. Factors contributing to the longer-lived (several hour) effects of ethanol on LTP; and 3. Factors contributing to the acute tolerance to ethanol-mediated LTP inhibition following slower increases in ethanol concentration. These studies will be done in rat hippocampal studies and will focus on the effects of ethanol and related modulators on glutamatergic and GABAergic transmission. The long-term goal of these studies is to identify ways to protect the nervous system from the adverse effects of ethanol on synaptic function and cognition. PUBLIC HEALTH RELEVANCE Alcohol is one of the most commonly abused drugs in the United States and is associated with both acute and long-term problems with memory processing. The goal of this project is to determine how alcohol alters communication between nerve cells to impair memory formation with the hope of developing better treatments for alcohol-induced memory problems.

描述（由申请人提供）：急性乙醇中毒与行为和认知症状相关，包括记忆处理问题。在某些情况下，乙醇中毒会导致完全无法处理新信息，这种情况被称为“停电”。了解乙醇如何改变认知和记忆对于确定保护神经系统免受药物短期和长期不良影响的方法非常重要。尽管哺乳动物神经系统中记忆处理的机制尚未完全了解，但目前的证据表明，海马谷氨酸突触的突触可塑性的使用依赖性形式，包括长时程增强（LTP）和长时程抑制（LTD），是相关的。在过去的几年里，我们的实验室研究了乙醇对大鼠海马切片 CA1 区突触传递和突触可塑性的急性影响。我们发现乙醇可强烈抑制突触 N-甲基-D-天冬氨酸受体 (NMDAR) 的特定亚型，该亚型也受到 NR1/NR2B 拮抗剂艾芬地尔的抑制。乙醇对 LTD 的阻断与这些突触 NMDAR 的阻断相关。对 LTP 的影响更加复杂和持久，并且涉及对 γ-氨基丁酸 (GABA) 介导的抑制传播的影响。在最近的研究中，我们发现增强 GABA 的神经类固醇有助于乙醇阻断 LTpreliminary 此外，乙醇阻断 LTP 的能力取决于乙醇的给药方式，急性应用高浓度阻断 LTP 并缓慢逐步增加乙醇浓度至高水平，导致一种急性耐受性。在这个项目中，我们将扩展这些初步观察并进行三组研究，这些研究将检查： 1. GABA 能神经类固醇如何促进乙醇对 LTP 的急性影响； 2. 导致乙醇对 LTP 产生较长寿命（几个小时）影响的因素； 3. 乙醇浓度缓慢增加后，导致对乙醇介导的 LTP 抑制产生急性耐受的因素。这些研究将在大鼠海马体研究中进行，重点关注乙醇和相关调节剂对谷氨酸能和 GABA 能传递的影响。这些研究的长期目标是找到保护神经系统免受乙醇对突触功能和认知的不利影响的方法。公共卫生相关性酒精是美国最常滥用的药物之一，与记忆处理的急性和长期问题有关。该项目的目标是确定酒精如何改变神经细胞之间的通讯以损害记忆形成，希望开发出更好的治疗方法来治疗酒精引起的记忆问题。