Deletion of GABAA Receptor α1 Subunit-containing Receptors Alters Responses to Ethanol and Other Anesthetics

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Abstract
GABAA receptors have been implicated in mediating several acute effects of ethanol including anxiolysis, ataxia, sedation/hypnosis, and anticonvulsant activity. Ethanol sensitivity of neurons has been associated with expression of α1 subunit-containing receptors. The objective of this study was to determine the contribution of α1 subunit containing receptors to ethanol responses in comparison to neurosteroids and other anesthetics using GABAA receptor α1 subunit knockout mice. Deletion of α1 subunit-containing receptors did not alter the anxiolytic, ataxic, anticonvulsant, or hypnotic effects of ethanol or acute functional tolerance to ethanol but did increase sensitivity to the locomotor-stimulating effects of ethanol. The ability of ethanol to potentiate muscimol-stimulated chloride uptake and ethanol clearance was also not altered following α1 subunit deletion. The anticonvulsant and hypnotic effects of neurosteroids as well as their potentiating effect on GABA-mediated Cl− uptake were unaltered in α1−/− mice. The hypnotic effect of pentobarbital, etomidate, and midazolam were reduced, whereas the effect of ketamine was enhanced in α1−/− mice. Thus, GABAA receptor α1 subunit-containing receptors appear to influence the motor-stimulating effect of ethanol and the sedative/hypnotic effects of some anesthetics, but not ethanol. These receptors do not appear to be necessary for most ethanol responses, suggesting involvement of other GABAA receptor subtypes or other targets altogether.

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