INTRACELLULAR STUDY OF ETHANOL EFFECTS ON BRAIN NEURONS

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Our objective 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 is to elucidate how ETOH alters information processing by central neurons in order to understand how brain function changes during human ETOH usage. The brain area selected for study is the locus coeruleus (LC) which is the largest noradrenergic nucleus in the brain and has extensive projections to many areas of the central nervous system (CNS). The LC has been implicated in a number of physiological functions such as: selective attention, arousal and sleep, response to stress, learning, and control of blood pressure. Both biochemical and electrophysiological studies suggest the involvement of noradrenergic systems in some of the effects of ETOH on CNS function and behavior. Intracellular recording will be used to investigate the effect of ETOH on the electrical activity of rat LC neurons in a brain slice preparation. Pontine 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. ETOH has several actions on LC neurons when applied in concentrations like those found in brain during mild intoxication through sedation (10-60 mM). ETOH inhibits the spontaneous "pacemaker" firing of LC neurons, causes an increase in a late phase of the spike afterhyperpolarization, hyperpolarizes the membrane and decreases input resistance. The ionic mechanisms which mediate these effects 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. The effects of ETOH and adenosine will be compared, to determine if they are mediated by common ionic mechanisms. Understanding the mechanisms mediating acute ETOH effects could lead to development of new agents for emergency treatment of alcoholic coma. Information about the mechanism of acute ETOH action is a necessary prerequisite to the ultimate goal of understanding the mechanisms by which ETOH's effects change under conditions of tolerance development and physical dependence, which in turn, should permit the rational development of therapeutic regimens for better treatment of habitual ETOH usage and the ETOH withdrawal syndrome.