Mechanisms of Alcohol Withdrawal

戒酒机制

• 批准号: 8100122
• 负责人: DWAYNE W GODWIN
• 金额: $ 31.69万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100122
• 关键词: A Mouse; Action Potentials; Acute; Affect; Agonist; Alcohol Withdrawal Seizures; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Animals; Antiepileptic Agents; Attenuated; Behavioral; Biology; Brain; Calcium; Calcium Channel; Cells; Central Nervous System Diseases; Cerebral cortex; Chronic; Clinical; Complex; Confusion; Data; Development; Diagnosis; Electroencephalography; Ethanol; Event; Exposure to; Frequencies; Functional disorder; Gene Expression; Gene Proteins; Generalized seizures; Genes; Goals; Hallucinations; Health; Heart; Hippocampus (Brain); Human; Hyperactive behavior; Incidence; Kindling (Neurology); Kinetics; Knock-out; Knockout Mice; Link; Liver; Lung; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Monitor; Mus; Neurons; Pattern; Pharmaceutical Preparations; Protein Isoforms; Protocols documentation; Regulation; Resistance; Resolution; Role; Seizures; Self Administration; Severities; Sleep; Structure; Symptoms; System; T-Type Calcium Channels; Testing; Thalamic Nuclei; Thalamic structure; Time; Tissues; Training; Tremor; Wild Type Mouse; Withdrawal; alcohol exposure; attenuation; channel blockers; cohort; experience; knockout animal; mouse model; nonhuman primate; problem drinker; protein expression; research study; response; transcription factor; vapor; voltage

DESCRIPTION (provided by applicant): Alcohol abuse, in combination with multiple alcohol withdrawal events, produces a phenomenon similar to kindling in subcortical structures. Depending on the duration of alcohol consumption and the number of withdrawal events the clinical symptoms of alcohol withdrawal can range from mild to gross tremors, hyperactivity, confusion, hallucinations, sleep disruption and seizures. These symptoms can worsen with each withdrawal event and complicate diagnosis and treatment. Underlying withdrawal seizure is an abnormal brain rhythm that is produced in the thalamus by neurons firing rhythmic bursts of action potentials. These bursts depend upon a class of T-type calcium channels that are expressed within the brain and periphery. Despite the similarities between alcohol withdrawal seizures and other generalized seizures of thalamic origin, the influence of ethanol on thalamic function during alcohol withdrawal is unknown. This is particularly important to understand because abnormal thalamic rhythms precede the generalization of abnormal rhythms in both the hippocampus and the cerebral cortex. The overall goal of this proposal is to determine cellular and molecular mechanisms underlying alterations in thalamic T-type calcium channels in response to multiple withdrawal events and how these contribute to alcohol withdrawal seizure. A mouse model will be used to explore these mechanisms because it possesses all three of the T-type calcium channel isoforms, and is a well-developed model for multiple withdrawal seizures. In addition, it will allow us to integrate a knockout of a highly ethanol-sensitive T-type channel isoform in our studies. In Aim 1, we propose to record withdrawal seizures and, using spike train analyses we have developed, to characterize the specific contribution of T-type channel burst discharges to the development of seizure. In Aim 2, we will characterize the molecular mechanisms underlying the development of burst firing in subcortical structures, and we will relate the incidence of bursts to the gene and protein increases we have observed in our preliminary studies. In Aim 3, we will use high resolution whole cell patch recordings to determine whether the increases in gene and protein expression we have observed produce simple increases in calcium currents, or more complex alterations in basic channel kinetics. PUBLIC HEALTH RELEVANCE We will examine the influence of ethanol on an ethanol-sensitive calcium channel that underlies alcohol withdrawal seizure. In addition to the brain, this channel is involved in the basic biology and dysfunction of the heart, lung and liver, and is expressed in certain cancers, thus studies of the molecular regulation of this channel are highly significant to human health generally, and are specifically relevant to the understanding of alcohol withdrawal.

描述(申请人提供)：酒精滥用，结合多次酒精戒断事件，会产生类似于皮质下结构点燃的现象。根据饮酒时间和戒断次数的不同，戒酒的临床症状从轻微到严重的震颤、多动、神志不清、幻觉、睡眠中断和癫痫发作不等。这些症状会随着每次戒断事件的发生而恶化，并使诊断和治疗复杂化。潜在的戒断发作是一种异常的大脑节律，由神经元发射有节奏的动作电位突发在丘脑产生。这些突发依赖于一类在大脑和外周表达的T型钙通道。尽管酒精戒断发作与其他起源于丘脑的全身性癫痫发作有相似之处，但乙醇在酒精戒断过程中对丘脑功能的影响尚不清楚。了解这一点特别重要，因为异常丘脑节律先于海马体和大脑皮层异常节律的泛化。这项建议的总体目标是确定丘脑T型钙通道变化的细胞和分子机制，以响应多个戒断事件，以及这些机制如何促进酒精戒断发作。将使用小鼠模型来探索这些机制，因为它拥有所有三种T型钙通道异构体，并且是一种发展良好的多次戒断发作的模型。此外，它将使我们能够在我们的研究中整合高度乙醇敏感的T型通道异构体的敲除。在目标1中，我们建议记录戒断发作，并使用我们开发的棘波序列分析来表征T型通道突发放电对癫痫发作发展的具体贡献。在目标2中，我们将描述皮层下结构中爆发式放电发生的分子机制，并将爆发式放电的发生与我们在初步研究中观察到的基因和蛋白质增加联系起来。在目标3中，我们将使用高分辨率全细胞斑片记录来确定我们观察到的基因和蛋白质表达的增加是导致钙电流的简单增加，还是基础通道动力学的更复杂的变化。公共卫生相关性我们将研究乙醇对酒精敏感的钙通道的影响，该通道是酒精戒断发作的基础。除大脑外，该通道还参与心脏、肺和肝脏的基本生物学和功能障碍，并在某些癌症中表达，因此研究该通道的分子调控对人类健康具有重要意义，尤其与了解酒精戒断有关。