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

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• 作者：Josipa Vlaini膰 ; ^{josipa.vlainic@irb.hr} ; Dubravka &Scaron ; vob &Scaron ; trac ; Maja Jazvin&scaron ; 膰ak Jembrek ; Toni Vlaini膰 ; Danka Peri膷i膰
• 关键词：Zolpidem ; Cerebellar granule cells ; GABAA receptor ; [3H]flunitrazepam binding ; Gene expression ; Tolerance
• 刊名：Life Sciences
• 出版年：2012
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：14 June, 2012
• 卷：90
• 期：23-24
• 页码：889-894
• 文件大小：307 K

摘要

Aims

Hypnotic zolpidem is a positive allosteric modulator of 纬-aminobutyric acid (GABA) action, with preferential although not exclusive binding for 伪1 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 渭M) treatment on GABA_A receptors on the membranes of rat cerebellar granule cells (CGCs) using [³H]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 [³H]flunitrazepam binding sites or the expression of 伪1 subunit mRNA. However, as shown by decreased GABA [³H]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.