Mechanisms of Alcohol Withdrawal

戒酒机制

• 批准号: 8325476
• 负责人: DWAYNE W GODWIN
• 金额: $ 6.41万
• 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/8325476
• 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（由申请人提供）：酗酒与多次戒酒事件的结合产生类似于皮层结构中的点燃的现象。根据饮酒的持续时间和戒断事件的数量，戒酒的临床症状范围从轻度到大的震颤，多动症，混乱，幻觉，睡眠中断和癫痫发作。每次戒断事件都会恶化这些症状，并使诊断和治疗变得复杂。潜在的戒断癫痫发作是一种异常的脑节律，在丘脑在丘脑中产生的神经元发射有节奏的动作电位。这些爆发取决于在大脑和周围表达的一类T型钙通道。尽管酒精戒断癫痫发作与丘脑起源的其他广泛性癫痫发作之间有相似之处，但乙醇对在戒酒期间丘脑功能的影响尚不清楚。理解这一点尤其重要，因为异常的丘脑节奏先于海马和大脑皮层中异常节奏的普遍性。该提案的总体目标是确定丘脑T型钙通道的细胞和分子机制，以响应多个戒断事件，以及这些如何有助于戒酒癫痫发作。小鼠模型将用于探索这些机制，因为它具有所有T型钙通道同工型的所有三个，并且是多次戒断癫痫发作的发达模型。此外，这将使我们能够在我们的研究中整合高度乙醇敏感的T型通道同工型的敲除。在AIM 1中，我们建议记录戒断癫痫发作，并使用我们开发的尖峰列车分析来表征T型通道爆发放电对发育发育的特定贡献。在AIM 2中，我们将表征皮层结构中爆发发射的发展的分子机制，并将爆发的发生率与我们在初步研究中观察到的基因和蛋白质增加相关。在AIM 3中，我们将使用高分辨率的全细胞斑块记录来确定我们观察到的基因和蛋白质表达的增加是在基本通道动力学中产生简单的钙电流增加，还是更复杂的变化。公共卫生相关性，我们将研究乙醇对乙醇敏感的钙通道的影响，该通道是基于戒酒癫痫发作的基础。除了大脑外，该通道还参与了心脏，肺和肝脏的基本生物学和功能障碍，并且在某些癌症中表达，因此该通道的分子调节的研究通常对人类健康非常重要，并且与对酒精戒断的理解特别相关。