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

The effects of long-term exposure to, and subsequent withdrawal of, diazepa m or imidazenil (full and partial agonists of the benzodiazepine receptor, respectively) on the abundance of GABA, receptor subunit mRNAs and peptides were investigated in rat cerebellar granule cells in culture. Exposure of cells to 10 muM diazepam for 5 days significantly reduced the amounts of al pha (1) and gamma (2) subunit mRNAs, and had no effect on the amount of alp ha (4) mRNA. These effects were accompanied by a decrease in the levels of alpha (1) and gamma (2) protein and by a reduction in the efficacy of diaze pam with regard to potentiation of GABA-evoked Cl- current. Similar long-te rm treatment with 10 muM imidazenil significantly reduced the abundance of only the gamma S-2 subunit mRNA and had no effect on GABA(A) receptor funct ion. Withdrawal of diazepam or imidazenil induced a marked increase in the amount of a, mRNA; withdrawal of imidazenil also reduced the amounts of alp ha (1) and gamma (2) mRNAs. In addition, withdrawal of diazepam or imidazen il was associated with a reduced ability of diazepam to potentiate GABA act ion. These data give new insights into the different molecular events relat ed to GABA, receptor gene expression and function produced by chronic treat ment and withdrawal of benzodiazepines with full or partial agonist propert ies. (C) 2001 Elsevier Science BY All rights reserved.