engleski

Differential effect of short- and long-term zolpidem treatment on recombinant alpha1beta2gamma2s subtype of GABA-A receptors

The aim of this study was to explore the mechanisms that underlie adaptive changes in GABA-A receptors following their short-term and long-term exposure to hypnotic zolpidem, the non-benzodiazepine agonist of benzodiazepine binding sites. Such studies might be important since the prescription of zolpidem is increasing and prolonged zolpidem treatment, as recently shown, induces tolerance (Vlainić and Peričić, Neuropharmacol, 56:1124-30, 2009). Human embryonic kidney (HEK 293) cells stably expressing recombinant alpha1beta2gamma2s GABA-A receptors were exposed to zolpidem (1 and 10 microM) for 2 h on one, two or three consecutive days or continuously for 48 h. Radioligand binding studies were used to determine the parameters of [3H]flunitrazepam ([3H]FNZ) binding sites. A single (2 h) or repeated (2 or three days for 2 h daily) exposure of cells to zolpidem did not affect either the maximum number (Bmax) or the affinity (Kd) of [3H]FNZ binding sites. Addition of GABA enhanced [3H]FNZ binding to membranes obtained from control and zolpidem treated cells in a concentration-dependent manner, but there was no difference in either the potency (EC50) or efficacy (Emax) of GABA to potentiate [3H]FNZ binding. On the contrary, prolonged occupation (48 h) of benzodiazepine binding sites by zolpidem (10 microM) produced an up-regulation (~150%) of [3H]FNZ binding sites with no change in their affinity, as well as the functional uncoupling between GABA and benzodiazepine binding sites, as evidenced by a decreased ability of GABA to stimulate [3H]FNZ binding. The results suggest that, in our model, the continuous, but not intermittent short-term exposure of cells to zolpidem is able to induce adaptive changes in GABA-A receptors possibly related to development of tolerance and dependence. These changes are not substantially different from those obtained after prolonged exposure of cells to high doses of classical benzodiazepines (Švob Štrac et al., Brain Res. 1246:29-40, 2008).

zolpidem ; recombinant GABA-A receptor ; ligand binding

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