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 concentr ations of ethanol (10-100 mM) can potentiate, inhibit, or have no effe ct on GABA(A) receptor-mediated synaptic responses in this brain regio n. The essential determinants of ethanol sensitivity have not been def ined; however, GABA(A) receptor subunit composition, as well as posttr anslational modifications of these receptors, have been suggested as i mportant factors in conferring ethanol sensitivity to the GABA, recept or complex. Multiple types of GABA(A) receptor-mediated synaptic respo nses have been described within individual hippocampal CA1 neurons. Th ese responses have been shown to differ in some of their physiological and pharmacological properties. In the present study we tested the hy pothesis 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) an d within the stratum lacunosum-moleculare (distal) activated nonoverla pping populations of GABAA receptors on rat hippocampal CA1 neurons. P roximal inhibitory postsynaptic currents (IPSCs) decayed with a single time constant and were significantly potentiated by ethanol at all co ncentrations tested (40, 80, and 160 mM). Distal IPSCs had slower deca y rates that were often described better by the sum of two exponential s and were significantly less sensitive to ethanol at all concentratio ns tested. Three other allosteric modulators of GABA(A) receptor funct ion with well-defined GABA(A) receptor subunit requirements. pentobarb ital, flunitrazepam, and zolpidem, potentiated proximal and distal GAB A(A) IPSCs to the same extent. These results demonstrate that the etha nol sensitivity of GABA(A) receptors can differ, not only between brai n regions but within single neurons. These findings offer a possible e xplanation for the conflicting results of previous studies on ethanol modulation of GABA(A) receptor-mediated synaptic transmission in rat h ippocampal CA1 neurons.