INTEGRATIVE NEUROBIOLOGY OF ALCOHOL WITHDRAWAL SEIZURES

描述：（改编自研究者摘要） 乙醇戒断综合神经生物学（ETX） 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进行微导线记录， 将ETX过程中的特定惊厥行为与离散异常 大脑特定区域神经元放电的变化。 的 神经生理学和行为学的相关性， ETX网络中涉及的结构需要完成我们的 知识 我们认为，体内整合方法是非常重要的， 有价值，因为ETX发作的性质严重依赖于 完整的大脑网络负责这种现象。 网络核心 在其他缉获中有很大的牵连，特别是 那些表现出强直-阵挛（大发作样）惊厥发作的患者， 在人体内的ETX过程中最为普遍。 这些结构中的神经元 响应多种感官形式，包括视觉输入， 与触发人类内毒素癫痫发作有直接关系 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态（视觉、听觉和处理）， 将这些变化与ETX期间的离散惊厥行为相关联。 的 用新的抗惊厥药选择性地改变这些变化的能力， 影响GABA或兴奋性氨基酸（EAA）的作用也将是 考察 总体假设是，异常放电模式表现为 上级丘和导水管周围深层神经元 灰色（PAG），产生ETX的每个离散行为阶段 抽搐 这一建议将描绘特定的神经元的作用， 在这些后者的核机制，管理的产生和时间 癫痫发作的模式 本提案还将审查下列行动： 全身和局部微量注射抗惊厥药影响作用 GABA和EAA。 纠正这些神经元放电异常 这些物质产生的核将有助于建立 改善内毒素治疗。 具体的目的是评估DLSC或PAG神经元的反应和行为 在行为大鼠内毒素发作的各个阶段， 通过局灶性和全身性施用改变GABA或 EAA行动。 我们希望这些方法能产生新的见解， 控制乙醇诱发癫痫易感性的神经生物学机制 戒断和建议改进的方法来治疗酒精中毒。

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.