Low tolerance and dependence liabilities of etizolam: Molecular, functional, and pharmacological correlates

The effects of prolonged exposure to and subsequent withdrawal of the thienotriazolobenzodiazepine etizolam on gamma-aminobutyric acid (GABA) type A receptor gene expression and function were compared with those of the benzodiazepine lorazepam. Exposure of rat hippocampal neurons in culture to 10 mu M etizolam for 5 days reduced the amounts of alpha 5 and gamma 2S receptor subunit mRNAs, whereas etizolam withdrawal was associated with a persistent reduction in gamma 2S mRNA and an increase in alpha 2 and alpha 3 mRNAs. Neither chronic exposure to nor withdrawal of etizolam affected the acute modulatory effects of etizolam or lorazepam on GABA-evoked Cl- current. Treatment with 10 mu M lorazepam for 5 days reduced the amounts of a I and gamma 2S subunit mRNAs and increased that of alpha 3 mRNA, whereas lorazepam withdrawal was associated with persistence of the changes in alpha 3 and gamma 2S mRNAs and an increase in alpha 2 and alpha 4 mRNAs. Parallel changes in the abundance of alpha 1 and alpha 4 subunit proteins induced by chronic exposure to and withdrawal of lorazepam, but not etizolam, were detected by immunocytofluorescence analysis. Chronic lorazepam treatment resulted in a reversible reduction in the modulatory efficacy of this drug and conferred on flumazenil the ability to potentiate GABA-evoked Cl- current. The anticonvulsant action of etizolam was not altered in mice chronically treated with this drug, whereas lorazepam-treated animals became tolerant to the acute anticonvulsant effect of this benzodiazepine. These data suggest that etizolam is endowed with a reduced liability to induce tolerance and dependence compared with classical benzodiazepines. (c) 2005 Elsevier B.V. All rights reserved.