INTRACELLULAR STUDY OF ETHANOL EFFECTS ON BRAIN NEURONS

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The aim of the proposed research is to study the effects of ethanol (ETOH) on single neurons by intracellular recording in rat brain slices. The brain areas selected for study are the locus coeruleus, cerebral cortex and cerebellum, areas known to be sensitive to ETOH on the basis of extracellular recording studies in vivo. These areas are especially relevant to understanding alterations in REM sleep, antianxiety activity and ataxia caused by ETOH. Tissue slices (300Mu) will be mounted, totally submerged in a chamber for intracellular recording. ETOH will be applied in known concentrations in the bath or by micropressure ejection. Parameters to be measured include ETOH's effect on passive membrane properties (resting potential, resistance and time constant), and on active membrane properties (action potential shape, threshold and repetitive firing properties). We will test the hypothesis that at least part of ETOH's actions on these brain areas is due to a potentiation of the neurotransmitter GABA, by looking at the effect of ETOH on responses to applied GABA and on GABAergic synaptic transmission. The mechanism of action of ETOH will be examined including whether it exerts its effects by interacting with membrane lipids and/or the BDZ-GABA-receptor-ionophore complex. The acute actions of barbiturates, benzodiazepines (BDZ) and ETOH will be compared on the same neurons to determine whether these agents are acting by common or differing mechanisms. Electro-physiological correlates of tolerance at the single neuron level will be sought by comparing acute applications of ETOH to neurons from rats pretreated chronically with ETOH, to effects on neurons from untreated control animals. Electrophysiological correlates of the ETOH withdrawal syndrome will be sought by studying the electrophysiological properties of neurons from rats pretreated chronically and then withdrawn from ETOH. Naive tissue incubated in vitro with ETOH will be examined for signs of acute tolerance. Possible cross-tolerance between ETOH, barbiturates and BDZ, and the effects of these agents on neurons from rats going through ETOH withdrawal will also be studied. These studies should clarify the mechanisms underlying the acute and chronic actions of ETOH (i.e. tolerance, physical dependence and withdrawal) on CNS neurons and aid in understanding the ameliorative effects of BDZ and barbiturates in the treatment of ETOH withdrawal.