There has been conflicting data concerning the effects of ethanol on GABA/A receptor function. While biochemical and behavioral investigations have been supportive of ethanol influencing GABA responses, electrophysiological studies have provided mixed results with some investigations observing an enhancement of GABA inhibition by ethanol and others reporting no effect. Recently, our laboratory observed that ethanol enhanced GABA responses in the medial septum but not in the lateral septum. To explain the differences at these sites and the literature controversy, we propose that the cellular action of ethanol on GABA/A responses depends upon a specific molecular composition of the GABA/A receptor complex which varies at different sites in brain.
Three specific aims are proposed to explore this hypothesis. The first Specific Aim will identify the specific subunit composition of the GABA receptor complexes in the lateral and medial septum. This will be accomplished by measuring mRNA for the GABA/A subunits at these brain sites.
The Second Aim will determine the cellular location of sites having mRNA for the GABA/A receptor like that for the medial or lateral septum. In situ hybridization of the appropriate mRNA will be used to make this determination. Finally, the third Specific Aim will characterize electrophysiologically the effect of ethanol on responses to iontophoretically applied GABA at sites defined with in-situ hybridization as having GABA/A receptors like either the medial or lateral septum. This latter study will provide a direct test of our hypothesis. To complement the electrophysiological studies, various ligands binding to the GABA complex will be tested at the sites investigated electrophysiologically. This autoradiographic evaluation will provide an alternative approach by which ethanol's actions on GABA/A receptors can be predicted. This work is expected to clarify the actions of ethanol on CNS function.
Showing the most recent 10 out of 15 publications
