engleski

Dose-dependent effects of zolpidem in an in vitro study

Introduction: Imidazopyridine zolpidem is non- benzodiazepine hypnotic, which exerts its effects via benzodiazepine modulatory sites on GABA-A receptor. This drug is a positive allosteric modulator of GABA-A receptors with preferential, although not exclusive, binding for alpha1 containing receptors. The aim of this study was to explore adaptive changes in GABAA receptors since the prescription of zolpidem is increasing substantially and prolonged zolpidem treatment induces tolerance in mice (Vlainić and Peričić, Neuropharmacol 56:1124-30, 2009). Materials and methods: In order to evaluate the effects of zolpidem treatment we treated stably transfected HEK 293 cells expressing recombinant GABA-A receptors with various concentrations of zolpidem (0.01-10 µM) during 48 h. To assess the maximum number of benzodiazepine binding sites and functional status of receptors radioligand binding studies were performed (Vlainić et al., Naunyn- Schmiedebergs Arch Pharmacol 382:201-12, 2010). Results: The results revealed that the maximum number of [3H]flunitrazepam binding sites increases with the concentration of the drug and reached a significant level at a dose of 1 µM, and especially at 10 µM. However, the reduction in functional interaction between GABA and benzodiazepine binding sites on GABA-A receptor complex appeared only at a dose of 10 µM of zolpidem. Conclusions: If the allosteric uncoupling of binding sites at GABA-A receptor is responsible for the development of tolerance, as suggested, one might assume that zolpidem at high doses has a tendency for the development of tolerance during long-term use, similar to those of classical benzodiazepine - diazepam (Švob Štrac et al., Brain Res 1246:29-40, 2008).

GABA-A receptors; zolpidem; tolerance; radioligand binding studies

nije evidentirano