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NEUROPHARMACOLOGY

Effects of Ethanol on Tonic GABA Currents in Cerebellar Granule Cells and Mammalian Cells Recombinantly Expressing GABA_A Receptors

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois

The effects of ethanol on the GABA_A receptors, which are regarded as one of the most important target sites of ethanol, are very controversial, ranging from potentiation to no effect. The subunit-containing GABA_A receptors expressed in Xenopus oocytes were recently reported to be potently augmented by ethanol. We performed patch-clamp experiments using the cerebellar granule cells and mammalian cells expressing recombinant GABA_A receptors. In granule cells, the sensitivity to GABA increased from 7 to 11 days in vitro. Furosemide, an antagonist of 6-containing GABA_A receptors, inhibited GABA-induced currents more potently at 11 to 14 days than at 7 days. Ethanol at 30 mM had either no effect or an inhibitory effect on currents induced by low concentrations of GABA in granule cells. On 42, 62, or 63GABA_A receptors expressed in Chinese hamster ovary cells, ethanol at 10, 30, and 100 mM had either no effect or an inhibitory effect on GABA currents. Ethanol inhibition of GABA_A receptor was observed in all of the subunit combinations examined. In contrast, the perforated patch-clamp method to record the GABA currents revealed ethanol effects on the 62 subunits ranging from slight potentiation to slight inhibition. Ethanol seems to exert a dual action on the GABA_A receptors and the potentiating action may depend on intracellular milieu. Thus, the differences between the GABA_A receptors expressed in mammalian host cells and those in Xenopus oocytes in the response to ethanol might be due to changes in intracellular components under patch-clamp conditions.

Address correspondence to: Dr. Toshio Narahashi, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611-3008. E-mail: narahashi{at}northwestern.edu

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