Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

Abstract

Aim: Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABA A 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 GABA A receptors following short and long-term exposure to zolpidem in vitro. Methods: Human embryonic kidney (HEK) 293 cells stably expressing recombinant α1β2γ2s GABA A receptors were exposed to zolpidem (1 and 10 μmol/L) for short-term (2 h daily for 1, 2, or 3 consecutive days) or long-term (continuously for 48 h). Radioligand binding studies were used to determine the parameters of Conclusion:The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive changes in GABA A receptors that could be related to the development of tolerance and dependence.

Correlates of Dependence and Beliefs About the Use of Hypnotics Among Zolpidem and Zopiclone Users

“…Previous studies have also indicated that high dosages (Liappas et al, 2003) and long-term use (Vlainić et al, 2012) of zolpidem may reduce its selectivity for GABA-A receptors, and demonstrated that the anxiolytic and stimulating action of classic BZDs (Vlainić et al, 2012) may increase the likelihood of dependence. However, high dosages and long-term use of Z-drugs may result in the development of tolerance to Z-drugs, after which users may perceive that hypnotics are less effective for sleep, and must continue using hypnotics to avoid discomfort.…”

“…Long-term use and high daily dosages of hypnotics have been associated with tolerance and dependence on both BZDs (Andersen & Frydenberg, 2011;Manthey et al, 2012) and zolpidem (Liappas et al, 2003;Vlainić, Jembrek, Vlainić, Strac, & Peričić, 2012). Having a history of drug and alcohol dependence can also increase the risks of both zolpidem (Hajak et al, 2003) and BZD dependence (Manthey et al, 2012).…”

GABA Receptors: Pharmacological Potential and Pitfalls

“…Regarding development of tolerance and dependence to benzodiazepine-site ligands after prolonged administration, diverse effects at the molecular and cellular level have been described, including receptor desensitization and changes in the number and subunit composition of surface GABAA receptors, often leading to decreased ability of benzodiazepines to potentiate effects of GABA [17,[119][120][121][122][123][124].…”

Dependence, misuse, and beliefs regarding use of hypnotics by elderly psychiatric patients taking zolpidem, estazolam, or flunitrazepam

“…Although zolpidem is thought to be a safe hypnotic with low dependence or abuse potential (Soyka et al, 2000), numerous studies have reported that dependence or abuse may develop after taking high-dose zolpidem continuously (Victorri-Vigneau et al, 2007). Continuous zolpidem exposure can induce adaptive changes in GABA-A receptors that could be related to the development of tolerance and dependence (Vlainić et al, 2012). Meanwhile, supratherapeutic doses of zolpidem may cause complex sleep behaviors (Hwang et al, 2010) and memory loss (Liappas et al, 2003).…”