The effects of zolpidem treatment on GABA(A) receptors in cultured cerebellar granule cells: changes in functional coupling.

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.