Basis of variable sensitivities of GABAA receptors to ethanol

Background: The GABA(A) system is believed to be one of the crucial target sites for ethanol. However, in the literature, data using various preparations yielded controversial conclusions regarding the ethanol potency to modulate the activity of GABA(A) receptors. We have previously shown that the potency of n-alcohols to potentiate GABA-induced currents is correlated with their carbon chain length. This correlation was further compared among four cell types in an attempt to explain the variable potencies of ethanol to potentiate GABA responses. Methods: Whole-cell patch clamp experiments were performed to determine and compare the potencies of n-alcohols in potentiating GABA-induced currents in rat dorsal root ganglion (DRG) neurons, human embryonic kidney cells expressing the rat alpha 1 beta 2 gamma 2S or alpha 1 beta 2 gamma 2L subunits, and rat cortical neurons. Results: The GABA(A) receptors of the four cell types tested were all sensitive to n-alcohols, albeit with different potencies and efficacies. The effective concentration to increase GABA-induced currents to 125% of control (EC125) was correlated with the carbon chain length of n-alcohols, but slopes for this relationship are different among DRG neurons, the alpha 1 beta 2 gamma 2S, and crlp2y2L subunits. Thus, the potencies of lower alcohols such as ethanol differed among these cell types although higher alcohols such as n-octanol were almost equally potent. In cortical neurons, however, the relationship was shifted in the direction of longer carbon chains, indicating that their sensitivity was lower than those of the other three cell types. The ethanol EC125 values as obtained by experiments or those by extrapolation (in parenthesis) from the EC125-carbon chain length relationship were: 169 (103) mM for DRG neurons, 501 (333) mM for the alpha 1 beta 2 gamma 2L subunits, 781 (674) mM for the alpha 1 beta 2 gamma 2S subunits, and (1897) mM for cortical neurons. Conclusions: It was concluded that the GABA(A) receptors of these four cell types were basically sensitive to n-alcohols including ethanol but the sensitivity curve was shifted to the lower side in the order of decreasing sensitivity of DRG neurons > alpha 1 beta 2 gamma 2L > alpha 1 beta 2 gamma 2S > cortical neurons.