INTEGRATIVE NEUROBIOLOGY OF ALCOHOL WITHDRAWAL SEIZURES

酒精戒断性癫痫发作的综合神经生物学

• 批准号: 2894209
• 负责人: CARL L FAINGOLD
• 金额: $ 19.31万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-07 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2894209
• 关键词: GABA receptor; action potentials; anticonvulsants; body movement; brain electrical activity; brain mapping; convulsions; drug screening /evaluation; drug withdrawal; electrostimulus; ethanol; excitatory aminoacid; gamma aminobutyrate; generalized seizures; glutamate receptor; laboratory rat; membrane potentials; microinjections; neural information processing; neuropharmacology; periaqueductal gray matter; superior colliculus; synapses; tissue /cell culture

DESCRIPTION: (Adapted from the Investigator's Abstract) A thorough understanding of the integrative neurobiology of ethanol withdrawal (ETX) seizures is a vital approach to establishing the most selective therapy for ETX. Through the use of microwire recordings in behaving rats we can correlate specific convulsive behaviors during ETX with discrete aberrant changes in neuronal firing in specific brain regions. The neurophysiological and behavioral correlations for three of the brain structures implicated in the ETX network are needed to complete our knowledge. We believe the integrative in vivo approach is extremely valuable, because the nature of ETX seizures is critically dependent on the intact brain network responsible for this phenomenon. The network nuclei under investigation are strongly implicated in other seizures, particularly those that exhibit tonic-clonic (grand mal-like) convulsive seizures that are most prevalent during ETX in humans. Neurons in these structures respond to multiple sensory modalities, including visual inputs, which has direct relevance to the triggering of human ETX seizures. This proposal will delineate specific neuronal firing changes in response to three modalities (visual, auditory and handling) in these network structures and correlate these changes with discrete convulsive behaviors during ETX. The ability to modify these changes selectively with novel anticonvulsants that affect the action of GABA or excitant amino acids (EAAs) will also be examined. The Overall Hypothesis is that abnormal firing patterns are exhibited by neurons in the deep layers of superior colliculus (DLSC) and periaqueductal gray (PAG) that produce each discrete behavioral phase of the ETX convulsion. This proposal will delineate the roles of specific neuronal mechanisms in these latter nuclei that govern the generation and temporal pattern of seizure behaviors. This proposal will also examine the action of systemic and focal microinjection of anticonvulsants affecting the actions of GABA and EAAs. Correction of neuronal firing abnormalities in these nuclei produced by these agents will help to establish the basis for improved therapy of ETX. The specific aims will evaluate DLSC or PAG neuronal responses and behavior during each phase of ETX seizures in behaving rats and examine the changes produced by focal and systemic administration of agents that alter GABA or EAA actions. We expect these approaches to yield novel insights into the neurobiological mechanisms controlling seizure susceptibility during ethanol withdrawal and suggest improved approaches to the therapy of alcoholism.

描述：（改编自研究者的摘要）彻底的 了解乙醇戒断 (ETX) 的综合神经生物学 癫痫发作是建立最具选择性治疗的重要方法 ETX。 通过使用微丝记录老鼠的行为，我们可以 将 ETX 期间的特定惊厥行为与离散异常相关联 特定大脑区域神经元放电的变化。 这 大脑三个部分的神经生理学和行为相关性 需要 ETX 网络中涉及的结构来完成我们的 知识。 我们相信体内综合方法非常有效 有价值的，因为 ETX 缉获的性质严重依赖于 完整的大脑网络造成了这种现象。 网络核心 正在接受调查的物品与其他缉获案件密切相关，特别是 那些表现出强直阵挛（大发作样）惊厥性癫痫发作的患者 在人类 ETX 期间最为普遍。 这些结构中的神经元 对多种感官模式做出反应，包括视觉输入， 与触发人类 ETX 癫痫发作直接相关。 这个提议 将描绘响应三个的特定神经元放电变化 这些网络结构中的模式（视觉、听觉和处理） 将这些变化与 ETX 期间离散的惊厥行为联系起来。 这 使用新型抗惊厥药选择性改变这些变化的能力 影响 GABA 或兴奋性氨基酸 (EAA) 的作用也会 检查了。 总体假设是，异常的放电模式是由 上丘深层 (DLSC) 和导水管周围的神经元 灰色（PAG），产生 ETX 的每个离散行为阶段 抽搐。 该提案将描述特定神经元的作用 后面这些核中控制生成和时间的机制 癫痫发作行为模式。 该提案还将审查 影响作用的抗惊厥药的全身和局部显微注射 GABA 和 EAA。 纠正这些神经元放电异常 这些试剂产生的核将有助于奠定基础 改进了ETX的治疗。 具体目标将评估 DLSC 或 PAG 神经元反应和行为 在行为大鼠 ETX 癫痫发作的每个阶段并检查其变化 通过局部和全身施用改变 GABA 或 监管局的行动。 我们期望这些方法能够产生新的见解 控制乙醇期间癫痫易感性的神经生物学机制 戒断并建议改进酒精中毒的治疗方法。