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 microM etizolam for 5 days reduced the amounts of alpha5 and gamma2S receptor subunit mRNAs, whereas etizolam withdrawal was associated with a persistent reduction in gamma2S mRNA and an increase in alpha2 and alpha3 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 microM lorazepam for 5 days reduced the amounts of alpha1 and gamma2S subunit mRNAs and increased that of alpha3 mRNA, whereas lorazepam withdrawal was associated with persistence of the changes in alpha3 and gamma2S mRNAs and an increase in alpha2 and alpha4 mRNAs. Parallel changes in the abundance of alpha1 and alpha4 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.
Sanna
Enrico
E
Department of Experimental Biology, Section of Neuroscience, University of Cagliari, Cagliari, Italy. esanna@unica.it
Busonero
Fabio
F
Talani
Giuseppe
G
Mostallino
Maria Cristina
MC
Mura
Maria Luisa
ML
Pisu
Maria Giuseppina
MG
Maciocco
Elisabetta
E
Serra
Mariangela
M
Biggio
Giovanni
G
D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D018757:GABA Modulators / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007538:Isoniazid / Q000633:toxicity; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013462:Sulfur Radioisotopes; D014149:Tranquilizing Agents / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018757:GABA Modulators; D021122:Protein Subunits; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; D014149:Tranquilizing Agents; C037476:tert-butylbicyclophosphorothionate; C044610:etizolam; D008140:Lorazepam; D003975:Diazepam; D007538:Isoniazid