MOLECULAR-BASIS FOR REGIONALLY SPECIFIC ACTION OF ETHANOL ON GAMMA-AMINOBUTYRIC ACID(A) RECEPTORS - GENERALIZATION TO OTHER LIGAND-GATED ION CHANNELS

The present investigation provides evidence that there is neuroanatomi cal specificity for ethanol enhancement of gamma-aminobutyric acid (GA BA)-induced inhibition in mammalian brain and that the expression of a specific GABA(A) isoreceptor is associated with this regional action of ethanol. Ethanol enhanced responses to iontophoretically applied GA BA in the medial septum, inferior colliculus, substantia nigra reticul ata, ventral pallidum and the diagonal band of Broca. In contrast to t hese results, responses to GABA applied to cells in the lateral septum , ventral tegmental area and the hippocampus were not affected by etha nol. In those brain regions where ethanol enhanced responses to GABA, a high concentration of zolpidem binding was found, whereas zolpidem b inding was much lower or absent in brain regions where ethanol did not enhance GABA. These observations support the hypothesis that ethanol enhances GABA within specific regions of brain by affecting a GABA(A) receptor with specific structural components. From data obtained with in situ hybridization, there was a strong relationship between the reg ional distribution of zolpidem binding and the expression of specific mRNAs for the alpha-1, beta-2 and gamma-2 GABA(A) receptor subunits at sites where ethanol enhanced responses to GABA. The mRNA for the long and short variants of the gamma-2 subunit were found in brain regions both sensitive and insensitive to the action of ethanol on GABA-induc ed inhibition. These data were not able to address whether the gamma-2 long variant in combination with the alpha-1 and beta-2 subunits is e ssential for ethanol enhancement of responses to GABA. However, the ob servation that the long version of the gamma-2 subunit is present in b rain areas where ethanol did not affect GABA function suggests that th e presence of the long variant of the gamma-2 subunit alone is not suf ficient for ethanol's action to enhance responses to GABA. Rather it i s concluded that the appropriate combination of GABA(A) receptor subun its is critical for this action of ethanol. Because the GABA(A) recept or belongs to a superfamily of ligand-gated ion channels, the action o f ethanol was examined on responses to agonists acting on receptors li nked to other ion channels. As noted for GABA, local application of et hanol altered responses to NMDA, nicotine and glycine when applied to some, but not all, neurons. It is hypothesized that the action of etha nol to affect some, but not all, responses of agonists for the superfa mily of ligand-gated ion channel receptor is based upon specific struc tural components of these receptors, just as evidence suggests is the case for GABA(A) isoreceptors.