Cellular Mechanisms of Ethanol's Influence on Sleep

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DESCRIPTION (provided by applicant): Drinking alcohol makes you sleepy. For some insomniacs, this effect is the pathway to bedtime alcohol consumption and eventual abuse. Sleep disturbances are common in alcoholic patients, with a number of serious health consequences. The most prominent and best understood of brain rhythms are the spindle waves associated with Stage II sleep, and this specific form of sleep is enhanced in response to acute alcohol administration. Perhaps the most promising brain region in which to explore alcohol influences on sleep - the thalamus- has been so far ignored. The thalamus is a primary generator of sleep/wake cycles and the brain rhythms that are the hallmark of sleep staging. Slices of the ferret thalamus possess all of the necessary circuitry for the generation of spindle waves. The mechanisms underlying spindle wave generation are known to depend on specific synaptic activation patterns of GABAergic circuitry within the thalamus', with both ascending and descending control from the brainstem and cortex, respectively. GABAergic and glutamatergic systems (particularly NMDA) are known targets of ethanol, and synaptic transmission is therefore our primary target in this proposal. Ethanol has been shown to potentiate evoked GABAa IPSCs in a number of brain regions, via several known mechanisms, including enhancement of the underlying GABAa receptor-mediated channel conductance. NMDA influences are known to entrain thalamic rhythms. The following specific aims will determine the influence of ethanol on the spindle wave circuitry of the thalamus, and will examine GABAa, and NMDA mediated synaptic transmission as touchstones of these effects: Aim 1: We will examine the influence of ethanol on GABAa receptor-mediated IPSPs and IPSCs within the thalamus using intracellular recording techniques. We hypothesize that ethanol will potentiate the amplitude of GABAa IPSPs and IPSCs by postsynaptic mechanisms that favor the generation of spindle waves, as predicted by our preliminary modeling data. Aim 2: We will examine the influence of ethanol on NMDA receptor- mediated EPSPs and EPSCs within the thalamus. Stimulation of the corticothalamic pathway specifically activates glutamate receptors and can synaptically synchronize spindle waves. We hypothesize that ethanol will attenuate NMDA receptor-mediated potentials, disrupting cortical control of spindle waves, consistent with our preliminary data. Aim 3: We will examine the effect of ethanol on a low threshold calcium current that is vital to spindle oscillations. Our preliminary data show an enhancement of this current during ethanol exposure, which could underlie increases in sleep spindles by ethanol. This research is an opportunity to work out the mechanisms underlying reported acute perturbations of normal sleep by ethanol in a new, yet well-characterized and accessible model system. These acute changes may set the stage for disruption of sleep due to chronic abuse, disruptions that last well beyond withdrawal. Because the targets of ethanol to be examined here are vital links to ethanol's influence in other systems, our results will extend to basic mechanisms of ethanol effects in the CNS as a whole.