Sleep perturbations by ethanol play a key role in the progression of alcoholism, and are predictive of relapse. For some insomniacs, the sedative effects of ethanol are the pathway to bedtime alcohol consumption and eventual abuse. Continued abuse of ethanol leads to long-term changes in sleep circuitry that last well beyond the cessation of ethanol administration. The overall goal of this project is to determine the key molecular events that underlie cellular adaptation of sleep circuitry to alcohol, with the eventual goal of identifying novel drug targets for treatment of ethanol's disruption of normal sleep. The thalamus is a primary generator of sleep/wake cycles and the brain rhythms that occur during sleep. The best understood of these rhythms is the thalamic spindle oscillation associated with Stage II sleep, which is enhanced in response to acute alcohol administration. In alcoholics, spindle waves are diminished and are replaced with less-restful random eye movement (REM) sleep. Understanding the fate of spindle wave sleep is thus a vital question that directly relates to the reinforcement effects of ethanol, since some alcoholics return to drinking in an effort to improve the quality of their sleep. No laboratory has addressed the mechanism of these changes in a primate model, or in animals with well-characterized drinking schedules. The engine that allows spindle waves to flow through the brain is a low threshold calcium current, mediated by T-type calcium channels that come in three known varieties. We have recently shown that the T-channel transcript found in thalamic relay cells is exquisitely sensitive to ethanol, showing acute enhancement at the low end of physiologically meaningful ethanol concentrations (10-17mM). Amazingly, this current appears to be inhibited by concentrations of ethanol much above this range.
In Aim 1 of this project we will determine whether the T channel is functionally impaired in the dorsal lateral geniculate nucleus of chronic drinking animals by performing whole cell patch recordings in two preparations, monkeys and rats, in a condition of excessive drinking and in a condition near the peak of withdrawal.
In Aim 2, we will determine with patch recordings whether the T channel function is reduced in the thalamic reticular nucleus of chronic drinking animals. The experiments of Aim 3 will provide a complementary examination of the molecular expression patterns of T-type channels in monkeys and rats using quantitative RT-PCR techniques.
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