Low tolerance and dependence liabilities of etizolam: Molecular, functional, and pharmacological correlates
SANNA, ENRICO;BUSONERO, FABIO;TALANI, GIUSEPPE;SERRA, MARIANGELA;
2005-01-01
Abstract
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.Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.