Differential ethanol sensitivity of subpopulations of GABA(A) synapses onto rat hippocampal CA1 pyramidal neurons

The actions of ethanol on gamma-aminobutyric acid-A (GABA(A)) receptor-mediated synaptic transmission in rat hippocampal CA1 neurons remain controversial. Recent studies have reported that intoxicating concentrations of ethanol (10-100 mM) can potentiate, inhibit, or have no effect on GABA(A) receptor-mediated synaptic responses in this brain region. The essential determinants of ethanol sensitivity have not been defined; however, GABA(A) receptor subunit composition, as well as posttranslational modifications of these receptors, have been suggested as important factors in conferring ethanol sensitivity to the GABA, receptor complex. Multiple types of GABA(A) receptor-mediated synaptic responses have been described within individual hippocampal CA1 neurons. These responses have been shown to differ in some of their physiological and pharmacological properties. In the present study we tested the hypothesis that some of the disparate findings concerning the effects of ethanol may have resulted from differences in the ethanol sensitivity of GABA(A) receptor-mediated synapses on single CA1 pyramidal cells. Electrical stimulation adjacent to the stratum pyramidale(proximal) and within the stratum lacunosum-moleculare (distal) activated nonoverlapping populations of GABAA receptors on rat hippocampal CA1 neurons. Proximal inhibitory postsynaptic currents (IPSCs) decayed with a single time constant and were significantly potentiated by ethanol at all concentrations tested (40, 80, and 160 mM). Distal IPSCs had slower decay rates that were often described better by the sum of two exponentials and were significantly less sensitive to ethanol at all concentrations tested. Three other allosteric modulators of GABA(A) receptor function with well-defined GABA(A) receptor subunit requirements. pentobarbital, flunitrazepam, and zolpidem, potentiated proximal and distal GABA(A) IPSCs to the same extent. These results demonstrate that the ethanol sensitivity of GABA(A) receptors can differ, not only between brain regions but within single neurons. These findings offer a possible explanation for the conflicting results of previous studies on ethanol modulation of GABA(A) receptor-mediated synaptic transmission in rat hippocampal CA1 neurons.