Increase in expression of the GABA_A receptor alpha₄ 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 GABAA 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 α4 and γ2 subunit mRNAs, and had no effect on the amount of α1 mRNA. These effects were accompanied by a decrease in the levels of α1 and γ2 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 M imidazenil significantly reduced the abundance of only the γ2S subunit mRNA and had no effect on GABAA receptor function. Withdrawal of diazepam or imidazenil induced a marked increase in the amount of α4 mRNA; withdrawal of imidazenil also reduced the amounts of α1 and γ2 mRNAs. In addition, withdrawal of diazepam or imidazenil was associated with a reduced ability of diazepam to potentiate GABAA action. These data give new insights into the different molecular events related to GABAA receptor gene expression and function produced by chronic treatment and withdrawal of benzodiazepines with full or partial agonist properties