Differential effect of short- and long-term zolpidem treatment on recombinant alpha1 beta2 gamma2s subtype of GABA-A receptors
-
1
Rudjer Boskovic Institute, Division of molecular medicine, Netherlands
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, Neuropharmacology, 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).
Conference:
IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010.
Presentation Type:
Poster Presentation
Topic:
Cellular neuroscience
Citation:
Vlainic
J,
Jembrek
MJ and
PeriXcic
D
(2010). Differential effect of short- and long-term zolpidem treatment on recombinant alpha1 beta2 gamma2s subtype of GABA-A receptors.
Front. Neurosci.
Conference Abstract:
IBRO International Workshop 2010.
doi: 10.3389/conf.fnins.2010.10.00175
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
30 Apr 2010;
Published Online:
30 Apr 2010.
*
Correspondence:
Josipa Vlainic, Rudjer Boskovic Institute, Division of molecular medicine, Zagreb, Netherlands, josipa.vlainic@irb.hr