Background: Chronic ethanol administration has a plethora of physiological effects. Among the most consistently observed findings is a change in the expression pattern of gamma-aminobutyric acid type A (GABA(A)) receptor subunits in the rat brain cortex. These findings led to the hypothesis of "subunit substitution" to account for changes in receptor function without changes in receptor number.
Methods: We used subunit (alpha1 and alpha4) specific antibodies and a combination of immunohistochemistry and immunoblotting to examine subregions of cortex (prefrontal, cingulate, motor, parietal, and piriform) for their response to 2 weeks of forced ethanol administration.
Results: Overall, cortical immunoreactivity for the alpha1 subunit was decreased and for the alpha4 subunit increased whether measured immunohistochemically or by immunoblotting. Piriform cortex exhibited a bidirectional change in GABA(A) receptor alpha1 and alpha4 immunoreactivity, similar to that previously observed in preparations of whole cortex. However, in parietal cortex, declines in alpha1 immunoreactivity (55 +/- 12% control value [CV] and 88.3 +/- 4.3% CV; immunohistochemistry and immunoblotting, respectively) were not accompanied by concomitant increases in alpha4 immunoreactivity (104 +/- 8% CV and 116 +/- 9.3% CV; immunohistochemistry and immunoblotting, respectively). Conversely, alpha4 immunoreactivity increased in cingulate cortex (210 +/- 30% CV and 134 +/- 9.5% CV; immunohistochemistry and immunoblotting, respectively) without a decline in alpha1 immunoreactivity (90 +/- 4% CV and 91.3 +/- 3.9% CV; immunohistochemistry and immunoblotting, respectively). Prefrontal and motor cortex exhibited GABA(A) receptor subunit peptide alterations, but these changes varied with the method of analysis.
Conclusions: These findings demonstrate that ethanol dependence results in nonuniform changes in GABA(A) receptor subunit peptide levels across the rat brain cortex and suggest that mechanisms which subserve functional changes in receptor activity may vary in accordance with anatomic or cellular differences within the cortex.