engleski

The effect of prolonged zolpidem treatment on the recombinant alpha1beta2gamma2S GABA-A receptors stably expressed in HEK 293 cells.

Imidazopyridine zolpidem is the most widely prescribed non-benzodiazepine hypnotic, which exerts its effects via benzodiazepine modulatory sites on GABA-A receptor. This drug is a positive allosteric modulator of GABA-A receptors with preferential, although not exclusive, binding for receptors containing alpha1 subunit. It was suggested that drugs with high selectivity for alpha1 containing receptors produce after their chronic use less tolerance and dependence than classical benzodiazepines. In order to evaluate the effects of chronic zolpidem treatment on GABA-A receptors, we treated stably transfected human embryonic kidney (HEK 293) cells expressing recombinant alpha1beta2gamma2S GABA-A receptors, the most common type of GABA-A receptors found in the brain, with various concentrations of zolpidem (0.01-10 microM) during different period of time. Radioligand binding studies preformed under conditions previously described (Pericic et al. Naunyn-Schmiedeberg s Arch Pharmacol 375: 177-187, 2007) revealed that chronic exposure of cells to zolpidem (10 microM, 48 h) produced an up-regulation of [3H]flunitrazepam binding sites without changes in their affinity. The significant augmentation (105%) of benzodiazepine binding sites was accompanied by an up-regulation of the alpha1 subunit mRNA. Prolonged occupation of benzodiazepine binding site by 10 microM zolpidem produced also the functional uncoupling between GABA and benzodiazepine binding sites, as evidenced by a decreased ability of GABA to stimulate [3H]flunitrazepam binding. These changes are not substantially different from those obtained after prolonged exposure of cells to high doses of classical benzodiazepines.

zolpidem; recombinant GABA-A receptors; prolonged exposure; 3H-flunitrazepam binding; alpha1 subunit mRNA

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