PT - JOURNAL ARTICLE AU - Paolo Botta AU - Manuel Mameli AU - Kirsten L. Floyd AU - Richard A. Radcliffe AU - C. Fernando Valenzuela TI - Ethanol Sensitivity of GABAergic Currents in Cerebellar Granule Neurons Is Not Increased by a Single Amino Acid Change (R100Q) in the α<sub>6</sub> GABA<sub>A</sub> Receptor Subunit AID - 10.1124/jpet.107.127894 DP - 2007 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 684--691 VI - 323 IP - 2 4099 - http://jpet.aspetjournals.org/content/323/2/684.short 4100 - http://jpet.aspetjournals.org/content/323/2/684.full SO - J Pharmacol Exp Ther2007 Nov 01; 323 AB - Cerebellar granule neurons (CGNs) extrasynaptically express GABAA receptors containing α6βxδ subunits, which mediate tonic inhibitory currents. Although it has been shown that the function of these receptors is potently and directly enhanced by ethanol, this finding has not been reproducible across different laboratories. In outbred Sprague-Dawley rats, a naturally occurring arginine (R) to glutamine (Q) mutation in position 100 of the α6 subunit was reported to increase the ethanol sensitivity of these receptors. However, we did not detect an action of this mutation in selectively bred rats (alcohol-tolerant and alcohol-nontolerant). Consequently, we reexamined the effect of the mutation on ethanol sensitivity in Sprague-Dawley rats. Using patch-clamp electrophysiological techniques in cerebellar vermis parasagittal slices, we found that 25 mM ethanol increases the tonic current amplitude, tonic current noise, and spontaneous inhibitory postsynaptic current (sIPSC) frequency to a similar extent in α6-100R/100R and α6-100Q/100Q CGNs. Exposure to 80 mM ethanol increased the tonic current amplitude to a significantly greater extent in α6-100R/100R than in α6-100Q/100Q CGNs; however, the effects of 80 mM ethanol on the tonic current noise and sIPSC frequency were not significantly different between these groups. In the presence of tetrodo-toxin, a non-N-methyl-d-aspartate receptor antagonist, exogenous GABA, and a GABA transporter inhibitor, neither 8 nor 40 mM ethanol consistently affected tonic current amplitude or noise in α6-100R/100R or α6-100Q/100Q CGNs. Thus, the α6-R100Q GABAA receptor subunit polymorphism does not in-crease the acute ethanol sensitivity of extrasynaptic receptors, lending further support to the hypothesis that ethanol modulates these currents indirectly via a presynaptic mechanism. The American Society for Pharmacology and Experimental Therapeutics