Increase in expression of the GABA A receptor α 4 subunit gene induced by withdrawal of, but not by long-term treatment with, benzodiazepine full or partial agonists

Abstract

The effects of long-term exposure to, and subsequent withdrawal of, diazepam or imidazenil (full and partial agonists of the benzodiazepine receptor, respectively) on the abundance of GABA A receptor subunit mRNAs and peptides were investigated in rat cerebellar granule cells in culture. Exposure of cells to 10 μM diazepam for 5 days significantly reduced the amounts of α 1 and γ 2 subunit mRNAs, and had no effect on the amount of α 4 mRNA. These effects were accompanied by a decrease in the levels of α 1 and γ 2 protein and by a reduction in the efficacy of diazepam with regard to potentiation of GABA-evoked Cl − current. Similar long-term treatment with 10 μM imidazenil significantly reduced the abundance of only the γ 2S subunit mRNA and had no effect on GABA A receptor function. Withdrawal of diazepam or imidazenil induced a marked increase in the amount of α 4 mRNA; withdrawal of imidazenil also reduced the amounts of α 1 and γ 2 mRNAs. In addition, withdrawal of diazepam or imidazenil was associated with a reduced ability of diazepam to potentiate GABA action. These data give new insights into the different molecular events related to GABA A receptor gene expression and function produced by chronic treatment and withdrawal of benzodiazepines with full or partial agonist properties.