CHRONIC ETHANOL TREATMENT ALTERS BRAIN LEVELS OF GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR SUBUNIT MESSENGER-RNAS - RELATIONSHIP TO GENETIC-DIFFERENCES IN ETHANOL WITHDRAWAL SEIZURE SEVERITY

Chronic ethanol treatment is known to alter the function of the gamma-aminobutyric acid(A) (GABA(A)) benzodiazepine receptor complex. To determine if genetic differences in development of ethanol dependence are related to expression of GABA(A) receptor subunits, we measured whole brain levels of mRNA for the alpha-1, alpha-3, alpha-6, gamma-2S, gamma-2L and gamma-3-receptor subunits in withdrawal seizure-prone and -resistant (WSP and WSR, respectively) mice fed an ethanol-containing liquid diet or a control diet. Brain poly(A)+ RNA was converted to cDNA and amplified by the polymerase chain reaction using primers conserved among GABA(A) receptor subunits. Quantification was carried out by densitometric analysis of Southern blots generated using subunit-specific probes. Chronic ethanol treatment decreased the content of alpha-1 mRNA in WSP but not WSR mice and decreased the content of alpha-6 mRNA in WSR but not WSP mice. The content of gamma-3 mRNA was increased by chronic ethanol in both lines. In untreated mice, the WSP line had lower levels of alpha-3 and alpha-6 mRNA than the WSR line. Thus, a decrease in the content of alpha-1 mRNA is most clearly linked with development of withdrawal signs, although the amounts of alpha-6 and alpha-3 may also be important in the genetic differences between WSP and WSR mice. In contrast, levels of mRNA for gamma-2S and gamma-2L subunits do not appear to be altered in ethanol dependence.