REVERSIBLE MODIFICATION OF GABA(A) RECEPTOR SUBUNIT MESSENGER-RNA EXPRESSION DURING TOLERANCE TO DIAZEPAM-INDUCED COGNITION DYSFUNCTION

Benzodiazepines (BZs) that are endowed with full positive allosteric m odulatory (FAM) activity on GABA(A) receptors cause anterograde amnesi a in both animals and humans. In rats subjected to a delayed object re cognition test, diazepam, endowed with FAM activity, exerted an amnesi c action, whereas BZs endowed with partial allosteric modulatory (PAM) activity on GABA(A) receptors, such as imidazenil, failed to induce a mnesia, even if administered at doses five times higher than those equ ipotent to a standard anticonvulsant dose of diazepam (17.6 mu mol/kg/ os). After discontinuation of 14 days' treatment with vehicle, diazepa m, or imidazenil.(three times daily with increasing doses starting fro m 17.6 mu mol/kg/os for diazepam and 2.5 mu mol/kg/os for imidazenil), we compared the persistence of tolerance to the amnesic effect of dia zepam with the persistence of the changes in the content of four (alph a 1, alpha(5), gamma(2L), gamma(2S)) GABA(A) receptor subunit mRNAs in the fronto-parietal motor (FrPaM) cortex and the hippocampus. Rats re ceiving the long-term treatment with diazepam developed a tolerance to the amnesic effect of this drug and showed a decrease (30-50%) in the expression of mRNAs encoding for alpha(1), gamma(2L), gamma(2S) GABA( A) receptor subunits, an increase, by approximately 30%, of the expres sion of mRNA of the alpha(5) subunit in the FrPaM cortex and a decreas e, by approximately 25%, in the expression of mRNA, of the alpha(1) su bunit in the hippocampus. These changes of subunit mRNA expression and the tolerance to the amnesic effect of diazepam returned to control v alues 72 hr after termination of the longterm treatment with diazepam. No tolerance to the amnesic effect of diazepam and no changes in GABA (A) receptor subunit mRNA expression were found in rats undergoing lon g-term treatment with imidazenil. Copyright (C) 1996 Elsevier Science Ltd.