The overall objective of this project is to describe the acute effects of ethanol (ETOH) on the electrophysiological properties of single neurons in the mammalian brain and to examine the basic ionic mechanisms which mediate these effects on neuronal membranes. The ultimate goal of such studies is to elucidate how ETOH alters information processing by central neurons in order to understand how brain function changes during human ETOH usage. Intracellular recording will be used to investigate ETOH effects on noradrenergic neurons of the locus coeruleus (LC) and dopaminergic neurons of the ventral tegmental area (VTA) studied in rat brain slices. Slices (300 mu) will be mounted, totally submerged in a recording chamber. ETOH will be applied in known concentrations in the bath or by micropressure ejection. The LC is the largest noradrenergic nucleus in the brain and is involved in regulation of overall behavioral state, such as: arousal level, sleep/wakefulness, level of vigilance and selective attention. Anxiety and panic reactions may be associated with hyperfunction of the LC. These behavioral states are altered by ETOH, which causes sedation, impairs selective attention and has an anxiolytic effect. Dopaminergic neurons of the VTA appear to be important in mediating the rewarding effects of ETOH and therefore may be of crucial importance in the control of voluntary ETOH intake and abuse. ETOH, in concentrations within the behaviorally active range, causes inhibition of firing of LC neurons but increases the firing rate of VTA neurons. Membrane mechanisms responsible for these two different actions of ETOH will be examined in a series of experiments employing current clamp recording in conjunction with ionic substitution and use of specific channel blockers. Single-electrode voltage clamp will be used to identify the specific membrane currents affected by ETOH. Information about the mechanisms of acute ETOH action is a necessary prerequisite to understanding the mechanisms underlying the rewarding effects of ETOH, as well as how ETOH tolerance and physical dependence develop. This, in turn, should permit the rational development of therapeutic regimens for better treatment of habitual ETOH usage and the ETOH withdrawal syndrome.
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