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.
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