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Received for publication June 29, 2007.
Revised August 14, 2007.
Accepted for publication August 16, 2007.
6 GABAA Receptor Subunit
Cerebellar granule neurons (CGNs) extrasynaptically express GABAA receptors containing 
6
x
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 6 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 Non-Tolerant). Consequently, we re-examined 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 sIPSC frequency to a similar extent in 6-100R/R and 6-100Q/Q CGNs. Exposure to 80 mM ethanol increased the tonic current amplitude to a significantly greater extent in 6-100R/R than 6-100Q/Q CGNs; however, the effects of 80 mM ethanol on the tonic current noise and sIPSC frequency were not significantly different between the groups. In the presence of tetrodotoxin, a non-NMDA receptor antagonist, exogenous GABA, and a GABA transporter inhibitor, neither 8 nor 40 mM ethanol consistently affected tonic current amplitude or noise in 6-100R/R or 6-100Q/Q CGNs. Thus, the 6-R100Q GABAA receptor subunit polymorphism does not modulate the acute ethanol sensitivity of extrasynaptic receptors, lending further support to the hypothesis that ethanol modulates these currents indirectly via a presynaptic mechanism.
Key words:
alcohol, cerebellum, inhibition, intoxication, motor, tonic
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T. S. Otis Comments on "Ethanol Sensitivity of GABAergic Currents in Cerebellar Granule Neurons Is Not Increased by a Single Amino Acid Change (R100Q) in the {alpha}6 GABAA Receptor Subunit" J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 399 - 400. [Full Text] [PDF]
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