The effects of zolpidem treatment on GABAA receptors in cultured cerebellar granule cells: Changes in functional coupling

Abstract Aims Hypnotic zolpidem is a positive allosteric modulator of γ-aminobutyric acid (GABA) action, with preferential although not exclusive binding for α1 subunit-containing GABA A receptors. The pharmacological profile of this drug is different from that of classical benzodiazepines, although it acts through benzodiazepine binding sites at GABA A receptors. The aim of this study was to further explore the molecular mechanisms of GABA A receptor induction by zolpidem. Main methods In the present study, we explored the effects of two-day zolpidem (10 μM) treatment on GABA A receptors on the membranes of rat cerebellar granule cells (CGCs) using [ 3 H]flunitrazepam binding and semi-quantitative PCR analysis. Key findings Two-day zolpidem treatment of CGCs did not significantly affect the maximum number (B max ) of [ 3 H]flunitrazepam binding sites or the expression of α1 subunit mRNA. However, as shown by decreased GABA [ 3 H]flunitrazepam binding, two-day exposure of CGCs to zolpidem caused functional uncoupling of GABA and benzodiazepine binding sites at GABA A receptor complexes. Significance If functional uncoupling of GABA and benzodiazepine binding sites at GABA A receptors is the mechanism responsible for the development of tolerance following long-term administration of classical benzodiazepines, chronic zolpidem treatment may induce tolerance.