Abstract
Aim: To investigate whether long-term exposure to the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces adaptive changes of GABA<sub>A</sub> receptors related to the development of tolerance and dependence. Methods: We compared the parameters of [<sup>3</sup>H]DHEAS binding and the effects of DHEAS on [<sup>3</sup>H]flunitrazepam binding in the membranes of HEK 293 cells, nontransfected or stably transfected with recombinant α<sub>1</sub>β<sub>2</sub>γ<sub>2S</sub> GABA<sub>A</sub> receptors. In HEK 293 cells expressing α<sub>1</sub>β<sub>2</sub>γ<sub>2S</sub> GABA<sub>A</sub> receptors, we investigated the effects of long-term DHEAS treatment on the [<sup>3</sup>H]flunitrazepam and [<sup>3</sup>H]t-butylbicycloorthobenzoate ([<sup>3</sup>H]TBOB) binding and on their modulation with GABA. Results: DHEAS behaves as an allosteric antagonist of the recombinant α<sub>1</sub>β<sub>2</sub>γ<sub>2S</sub> GABA<sub>A</sub> receptors expressed in HEK 293 cells. Exposure of cells to 100 µmol/l DHEAS for 48 h did not change the number or affinity of benzodiazepine and convulsive binding sites. Long-term DHEAS treatment failed to affect functional allosteric interactions between GABA<sub>A</sub> receptor binding sites, as evidenced by an unchanged ability of GABA to stimulate or to inhibit [<sup>3</sup>H]flunitrazepam and [<sup>3</sup>H]TBOB binding, respectively. Conclusion: The findings that prolonged DHEAS treatment does not produce changes in GABA<sub>A</sub> receptor expression and functional coupling, assumed to underlie the development of tolerance and dependence, might have importance in the long-term therapy necessary for the observed beneficial effects of DHEAS.
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