The role of thalamic T-type calcium channels in ethanol withdrawal

丘脑T型钙通道在乙醇戒断中的作用

• 批准号: 7781388
• 负责人: John David Graef
• 金额: $ 3.12万
• 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: 2008-09-05 至 2010-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781388
• 关键词: Address; Affect; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Animal Model; Animals; Anxiety; Behavioral; Benzodiazepines; Brain; Calcium Channel Blockers; Cells; Cerebral cortex; Chronic; Clinical; Complement; Data; Development; Diagnosis; Electroencephalography; Ethanol; Ethosuximide; Event; Exhibits; Gene Expression; Generations; Genes; Hippocampus (Brain); Intervention; Kindling (Neurology); Kinetics; Knockout Mice; Link; Masks; Measures; Messenger RNA; Methods; Molecular; Monitor; Motor Seizures; Mus; Neurons; Patients; Pharmacotherapy; Physiological; Predisposition; Property; Protein Isoforms; Rehabilitation therapy; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Role; Seizures; Severities; Structure; Symptoms; T-Lymphocyte; T-Type Calcium Channels; Techniques; Thalamic structure; Time; Tonic - clonic seizures; Training; Up-Regulation; Whole-Cell Recordings; Withdrawal; Withdrawal Symptom; alcohol exposure; ascorbate; base; cohort; experience; inhibitor/antagonist; mouse model; mutant; neuronal excitability; null mutation; problem drinker; relating to nervous system; response; vapor; voltage

DESCRIPTION (provided by applicant): This training plan proposal is focused on determining the cellular and molecular alterations of low-threshold, voltage-gated calcium channels (T-type) that occur within the thalamus after multiple ethanol withdrawals. By linking these changes to the development of progressively more severe withdrawal symptoms, I hope to understand the effects of ethanol withdrawal on thalamic function. Identifying treatments that then target these channels may therefore present new and effective pharmacotherapies in the successful rehabilitation of alcoholic patients. To address these issues will require new training in technical and conceptual approaches to alcohol withdrawal. I will accomplish this by investigating three integrated aims. The first two aims will be to determine how T-type calcium channels contribute to underlying neuronal changes in response to a multiple ethanol exposure and withdrawal mouse model. In Aim 1, using real time RT-PCR, I will examine thalamic T-type channel gene expression levels in mice during and after multiple ethanol exposures in a vapor chamber. I hypothesize an increase in T-type channel gene expression during ethanol withdrawal, and that the degree of these increases will be directly related to the number of withdrawals. In Aim 2,1 will record whole cell T-type currents from midline thalamic neurons of mice exposed to multiple withdrawals. I hypothesize a concomitant, functionally relevant increase in T-type channel function, as well as alterations in channel kinetics which may underlie the increased susceptibility to seizures during ethanol withdrawal. Aim 3 will be to determine the effects of the T-type calcium channel inhibitors ethosuximide and ascorbate during ethanol withdrawal. I will monitor cortical EEC activity using brief spindle episodes as a direct measure of neuronal excitability, thus providing an indirect measure of withdrawal seizure susceptibility. I hypothesize a reduction in the amount spindle incidents in mice that have been administered ethosuximide and ascorbate. Alcohol withdrawal syndrome is a significant societal problem. This research proposal is important because it will provide me with the necessary training to understand the long-term molecular and physiological changes that occur in response to chronic ethanol exposure and subsequent withdrawal. Current treatments for alcohol withdrawal, such as benzodiazepines, only address the immediate symptoms and can mask underlying physiological changes occurring during multiple withdrawals that can give rise to more severe symptoms. A more precise understanding of the mechanisms involved in the progression of alcohol withdrawal syndrome offers a tremendous opportunity for identifying new adjunct pharmacological interventions that can aid in the successful treatment of alcohol withdrawal patients.

描述（由申请人提供）：本培训计划提案的重点是确定多次乙醇戒断后丘脑内发生的低阈值电压门控钙通道（t型）的细胞和分子改变。通过将这些变化与逐渐加重的戒断症状的发展联系起来，我希望了解乙醇戒断对丘脑功能的影响。因此，确定针对这些通道的治疗方法可能会为成功康复酒精患者提供新的有效药物治疗。要解决这些问题，就需要在戒酒的技术和概念方法方面进行新的培训。我将通过研究三个综合目标来实现这一点。前两个目标将是确定t型钙通道对多重乙醇暴露和戒断小鼠模型的潜在神经元变化的影响。在目标1中，使用实时RT-PCR，我将检查小鼠在蒸汽室多次乙醇暴露期间和之后的丘脑t型通道基因表达水平。我假设在乙醇戒断期间t型通道基因表达增加，并且这些增加的程度将与戒断的数量直接相关。在Aim 2中，我将记录多次脱瘾小鼠丘脑中线神经元的全细胞t型电流。我假设同时存在与功能相关的t型通道功能的增加，以及通道动力学的改变，这可能是乙醇戒断期间癫痫发作易感性增加的基础。目的3将是确定t型钙通道抑制剂乙氧亚胺和抗坏血酸在乙醇戒断期间的作用。我将使用短暂的纺锤体发作作为神经元兴奋性的直接测量来监测皮层脑电图的活动，从而提供一种间接测量戒断发作易感性的方法。我假设给老鼠注射了乙氧亚胺和抗坏血酸后，纺锤体事件的数量减少了。酒精戒断综合症是一个严重的社会问题。这项研究计划很重要，因为它将为我提供必要的培训，以了解长期乙醇暴露和随后的戒断所发生的长期分子和生理变化。目前对酒精戒断的治疗，如苯二氮卓类药物，只能解决眼前的症状，并可能掩盖在多次戒断期间发生的潜在生理变化，这些变化可能导致更严重的症状。对酒精戒断综合征进展机制的更精确理解为确定新的辅助药物干预提供了巨大的机会，可以帮助成功治疗酒精戒断患者。