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 γ-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 μM etizolam for 5 days reduced the amounts of α5 and γ2S receptor subunit mRNAs, whereas etizolam withdrawal was associated with a persistent reduction in γ2S mRNA and an increase in α2 and α3 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 μM lorazepam for 5 days reduced the amounts of α1 and γ2S subunit mRNAs and increased that of α3 mRNA, whereas lorazepam withdrawal was associated with persistence of the changes in α3 and γ2S mRNAs and an increase in α2 and α4 mRNAs. Parallel changes in the abundance of α1 and α4 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.