GABA A receptor subunit mRNA levels are differentially influenced by chronic FG 7142 and diazepam exposure

Abstract

Levels of mRNA for the α 1, γ 2 and β 1 subunits of the GABA A receptor complex were examined in rats maintained on a chronic, continuous schedule of exposure to the benzodiazepine inverse agonist FG 7142. The effect of chronic exposure to the benzodiazepine agonist diazepam was also examined on levels of γ 2 subunit mRNA. FG 7142 (2 mg/ml of 100% dimethyl sulfoxide (DMSO) or vehicle (100% DMSO) was administered continuously for 8 days in the right ventricle via an osmotic minipump. At the end of the eighth day of exposure, the brain was removed and cerebral cortex, cerebellum and hippocampus were dissected and mRNA prepared from each region. Levels of GABA A α 1 and γ 2 subunit mRNA were examined by Northern blot analysis with cDNA probes specific for these subunits. A significant increase in α 1 mRNA was measured in both cortex and hippocampus, but not in cerebellum, of rats chronically exposed to FG 7142 relative to vehicle-treated rats. A significant increase in γ 2 subunit mRNA in cortex was also evident in drug-treated rats; however, no change in γ 2 subunit mRNA was observed in either the hippocampus or cerebellum. Examination of GABA A β 1 subunit mRNA by solution hybridization using a β 1 riboprobe revealed no effect of chronic FG 7142 treatment on this subunit in either cortex, hippocampus or cerebellum. In rats chronically exposed to diazepam (21 days via silastic implants), levels of γ 2 subunit mRNA were significantly decreased in cortex, but not changed in either hippocampus or cerebellum. This data adds to a previous report of a decrease in GABA A α 1 subunit mRNA with no change in β 1 mRNA in rat cortex. The findings demonstrate that GABA A subunit mRNA is differentially regulated by chronic FG 7142 and diazepam exposure. The increase and decrease in specific mRNA subunits by FG 7142 and diazepam, respectively, may underlie or at least reflect a compensatory response of the GABA A receptor complex to chronic occupation by these ligands.