Benzodiazepines (BZs) that are endowed with full positive allosteric modulatory (FAM) activity on GABAA receptors cause
anterograde amnesia in both animals and humans. In rats subjected to a delayed object recognition test,
diazepam, endowed with FAM activity, exerted an amnesic action, whereas BZs endowed with partial allosteric modulatory (PAM) activity on GABAA receptors, such as
imidazenil, failed to induce
amnesia, even if administered at doses five times higher than those equipotent to a standard
anticonvulsant dose of
diazepam (17.6 mumol/kg/os). After discontinuation of 14 days' treatment with vehicle,
diazepam, or
imidazenil (three times daily with increasing doses starting from 17.6 mumol/kg/os for
diazepam and 2.5 mumol/kg/os for
imidazenil), we compared the persistence of tolerance to the amnesic effect of
diazepam with the persistence of the changes in the context of four (alpha 1, alpha 5, gamma 2L, gamma 2S) GABAA receptor subunit mRNAs in the fronto-parietal motor (FrPaM) cortex and the hippocampus. Rats receiving 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 GABAA receptor subunits, an increase, by approximately 30%, of the expression of
mRNA of the alpha 5 subunit in the FrPaM cortex and a decrease, by approximately 25%, in the expression of
mRNA, of the alpha 1 subunit in the hippocampus. These changes of subunit
mRNA expression and the tolerance to the amnesic effect of
diazepam returned to control values 72 hr after termination of the long-term treatment with
diazepam. No tolerance to the amnesic effect of
diazepam and no changes in GABAA receptor subunit
mRNA expression were found in rats undergoing long-term treatment with
imidazenil.