Differential effects of short- and long-term zolpidem treatment on recombinant allβ2y2s subtype of GABAA receptors in vitro  

作　　者：Josipa VLAINIC Maja Jazvinscak JEMBREK Toni VLAINIC Dubravka Svob STRAC Danka PERICIC 

机构地区：[1]Ruder Boskovic Institute, Division of Molecular Medicine, Laboratory ofMolecularNeuropharmacology, POB 180, Zagreb, Croatia

出　　处：《Acta Pharmacologica Sinica》2012年第12期1469-1476,共8页中国药理学报（英文版）

摘　　要：Aim： Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABAA receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABAA receptors following short and long-term exposure to zolpidem in vitro. Methods： Human embryonic kidney （HEK） 293 cells stably expressing recombinant （x1132y2s GABAA receptors were exposed to zolpi- dem （1 and 10 pmol/L） for short-term （2 h daily for 1, 2, or 3 consecutive days） or long-term （continuously for 48 h）. Radioligand bind- ing studies were used to determine the parameters of [3H]flunitrazepam binding sites. Results： A single （2 h） or repeated （2 h daily for 2 or 3 d） short-term exposure to zolpidem affected neither the maximum number of [3H]flunitrazepam binding sites nor the affinity. In both control and short-term zolpidem treated groups, addition of GABA （1 nmol/L-1 mmol/L） enhanced [3H]flunitrazepam binding in a concentration-dependent manner. The maximum enhancement of [3H]flunitraze- pam binding in short-term zolpidem treated group was not significantly different from that in the control group. In contrast, long-term exposure to zolpidem resulted in significantly increase in the maximum number of [3H]flunitrazepam binding sites without changing the affinity. Furthermore, long-term exposure to zolpidem significantly decreased the ability of GABA to stimulate [3H]flunitrazepam bind- ing. Conclusion： The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive chanRes in GABA, receptors that could be related to the development of tolerance and dependence.Aim： Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABAA receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABAA receptors following short and long-term exposure to zolpidem in vitro. Methods： Human embryonic kidney （HEK） 293 cells stably expressing recombinant （x1132y2s GABAA receptors were exposed to zolpi- dem （1 and 10 pmol/L） for short-term （2 h daily for 1, 2, or 3 consecutive days） or long-term （continuously for 48 h）. Radioligand bind- ing studies were used to determine the parameters of [3H]flunitrazepam binding sites. Results： A single （2 h） or repeated （2 h daily for 2 or 3 d） short-term exposure to zolpidem affected neither the maximum number of [3H]flunitrazepam binding sites nor the affinity. In both control and short-term zolpidem treated groups, addition of GABA （1 nmol/L-1 mmol/L） enhanced [3H]flunitrazepam binding in a concentration-dependent manner. The maximum enhancement of [3H]flunitraze- pam binding in short-term zolpidem treated group was not significantly different from that in the control group. In contrast, long-term exposure to zolpidem resulted in significantly increase in the maximum number of [3H]flunitrazepam binding sites without changing the affinity. Furthermore, long-term exposure to zolpidem significantly decreased the ability of GABA to stimulate [3H]flunitrazepam bind- ing. Conclusion： The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive chanRes in GABA, receptors that could be related to the development of tolerance and dependence.

关 键 词：GABAA receptor HEK 293 cells ZOLPIDEM [3H]flunitrazepam binding 

分 类 号：Q424[生物学—神经生物学] Q577[生物学—生理学]