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NEUROPHARMACOLOGY

Ethanol Modulates Synaptic and Extrasynaptic GABA_A Receptors in the Thalamus

Department of Anesthesiology, C. V. Starr Laboratory for Molecular Neuropharmacology, Weill Cornell Medical College, New York, New York (F.J., N.L.H.); and Departments of Anesthesiology and Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania (D.C., G.E.H.)

Drinking alcohol is associated with the disturbance of normal sleep rhythms, and insomnia is a major factor in alcoholic relapse. The thalamus is a brain structure that plays a pivotal role in sleep regulation and rhythmicity. A number of studies have implicated GABA_A receptors (GABA_A-Rs) in the anxiolytic, amnestic, sedative, and anesthetic effects of ethanol. In the present study, we examined the effects of ethanol on both synaptic and extrasynaptic GABA_A-Rs of relay neurons in the thalamus. We found that ethanol (50 mM) elicits a sustained current in thalamocortical relay neurons from the mouse ventrobasal thalamus, and this current is associated with a decrease in neuronal excitability and firing rate in response to depolarization. The steady current induced by ethanol was totally abolished by gabazine and was absent in relay neurons from GABA_A-R ₄ subunit knockout mice, indicating that the effect of ethanol is to enhance tonic GABA-mediated inhibition. Ethanol (50 mM) enhanced the amplitude of tonic inhibition by nearly 50%. On the other hand, ethanol had no effect on spontaneous or evoked inhibitory postsynaptic currents (IPSCs) at 50 mM but did prolong IPSCs at 100 mM. Ethanol had no effect on the paired-pulse depression ratio, suggesting that the release of GABA from presynaptic terminals is insensitive to ethanol. We conclude that ethanol, at moderate (50 mM) but not low (10 mM) concentrations, can inhibit thalamocortical relay neurons and that this occurs mainly via the actions of ethanol at extrasynaptic GABA_A-Rs containing GABA_A-R ₄ subunits.

Address correspondence to: Dr. Neil Harrison, Dept. of Anesthesiology, Weill Cornell Medical College, 1300 York Avenue, Room A-1050, New York, NY 10065. E-mail: neh2001{at}med.cornell.edu