INTEGRATIVE NEUROBIOLOGY OF ALCOHOL WITHDRAWAL SEIZURES

描述：(改编自《调查者摘要》) 乙醇戒断(ETX)综合神经生物学的认识 癫痫发作是建立最具选择性的治疗方法的重要途径 ETX。通过对行为正常的大鼠使用微线记录，我们可以 ETX中特定的惊厥行为与离散异常的关系 特定脑区神经元放电的变化。这个 三个大脑的神经生理学和行为的相关性 ETX网络中涉及的结构需要完成我们的 知识。我们认为体内一体化的方法是非常 有价值，因为ETX发作的性质严重依赖于 完整的大脑网络是造成这种现象的原因。网络核心 正在调查中的人与其他癫痫发作有很大牵连，特别是 表现为强直阵挛(大发作样)惊厥性发作的患者 在人类ETX期间最常见。这些结构中的神经元 对多种感觉模式做出反应，包括视觉输入，这具有 与人类ETX癫痫的触发直接相关。这项建议 将描绘特定的神经元放电变化，以响应三个 这些网络结构中的模式(视觉、听觉和处理)以及 将这些变化与ETX期间离散的惊厥行为相关联。这个 使用新型抗惊厥药物选择性地改变这些变化的能力 影响GABA或兴奋性氨基酸(EaaS)的作用也会 检查过了。 总体假设是异常放电模式表现为 上丘和中脑导水管周围深层神经元 产生ETX的每个离散行为阶段的灰色(PAG) 抽搐。这项提议将描述特定神经元的作用。 在后两个核团中控制发生和时间的机制 癫痫发作行为的模式。这项提案还将审查 全身性和局灶性微量注射影响作用的抗惊厥药物 GABA和EaaS。矫正这些患者的神经元放电异常 这些试剂产生的原子核将有助于为 改进ETX的治疗方法。 特定的目标将评估DLSC或PAG神经元的反应和行为 在ETX发作的各个阶段，行为大鼠，并检查其变化 通过局部和系统地给药改变GABA或 地产代理监管局的行动。我们希望这些方法能够产生对 控制酒精发作敏感性的神经生物学机制 戒酒并建议改进酒精中毒的治疗方法。

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.