The effects of ethanol exposure on mammalian central nervous system function will be pursued using both extracellular recording of action potential activity from single neurons as well as evoked potentials, and intracellular recording of membrane properties. Recordings will be carried out in vivo in the intact brain in situ, in multiple brain grafts in oculo, and in brain slices as well as in extricated intraocular brain grafts in vitro. In addition to our studies of ethanol effects in rodent brain, we will study ethanol actions on human neurons using in oculo brain xenografts. Studies will focus on genetic variants manifesting differential alcohol-related behaviors as model systems for examining acute ethanol actions as well as for studying ethanol dependence and withdrawal. Our approach is to use genetic and pharmacological techniques to independently manipulate the behavioral effects and neuronal actions of ethanol. We are currently most interested in ethanol interactions with norepinephrine, dopamine, excitatory amino acids, and GABA in locus coeruleus, hippocampus and cerebellum. We propose to extend these studies to the dopaminergic ventral tegmental area and its target areas. The long- term objectives of this research program are three fold. First, electrophysiological and in vivo electrochemical techniques will be used both to characterize acute neuronal responses to ethanol as direct membrane effects, modulatory interactions with synaptic inputs, or alterations in the activity of neuronal pathways. Second, changes in neuronal responses to ethanol, as well as functional changes in neurotransmitter systems, will be determined after induction of ethanol dependence and withdrawal. Finally, using selectively bred and transgenic genetic variants, ethanol- induced electrophysiological responses will be correlated with alcohol- induced behaviors. A greater understanding of how ethanol alters CNS function should furnish new insights into the problems of alcohol intoxication and alcoholism.
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