GABAA, Receptor α1, α4, and β3 Subunit mRNA and Protein Expression in the Frontal Cortex of Human Alcoholics

Abstract

Animal studies have shown that chronic ethanol consumption produces physical dependence upon ethanol and alters gamma-aminobutyric acid-A (GABA(A)) receptor subunit gene expression in brain. Although extensive investigation has been conducted in animal models, relatively little work has been performed directly on human alcoholic brain tissue to determine if there are alterations in GABA(A) receptor gene expression. In this study, GABA(A) receptor alpha1, alpha4, and beta3 subunit mRNA and peptide expression in postmortem frontal cortex from human alcoholics (n = 15) and age- and sex-matched controls (n = 13) were measured by quantitative, competitive reverse transcription polymerase chain reaction and Western blot analysis. GABA(A) receptor beta3 subunit mRNA expression was 35% greater (p < 0.05) in alcoholics, compared with nonalcoholic controls. We found no significant difference in alpha1 and alpha4 subunit mRNA levels between groups. However, there was a trend toward greater (21%) alpha1 subunit mRNA expression. There was no difference in alpha1, alpha4, or beta2/3 subunit peptide levels in frontal cortex between controls and alcoholics. Neither the age of the subjects nor the postmortem interval correlated with mRNA or peptide levels. Blood ethanol content also did not correlate with mRNA or peptide expression in alcoholic samples. These data suggest that GABA(A) receptor adaptations, resulting from prolonged alcohol consumption in human alcoholics, may differ from animal models of alcohol dependence. These differences may be related to the longevity of alcohol exposure in human alcoholics, as well as variability in the dependence/withdrawal state of the human subjects. Therefore, further studies in human postmortem brain tissue are warranted.