engleski

Modulation of recombinant GABA-A receptors by neurosteroid dehydroepiandrosterone sulphate

Aim was to investigate whether long-term exposure to neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces adaptive changes of GABA-A receptors related to the development of tolerance and dependence. We compared the parameters of [3H]DHEAS binding and the effects of DHEAS on [3H]flunitrazepam binding in the membranes of HEK 293 cells, nontransfected or stably transfected with recombinant α1β2γ2S GABA-A receptors. In HEK 293 cells expressing α1β2γ2S GABA-A receptors we investigated the effects of long-term DHEAS treatment on the [3H]flunitrazepam and [3H]TBOB binding and on their modulation with GABA. DHEAS behaves as an allosteric antagonist of the recombinant α1β2γ2S GABA-A receptors expressed in HEK 293 cells. Exposure of cells to 100 microM DHEAS for 48 h have not changed the number or affinity of benzodiazepine and convulsive binding sites. Long-term DHEAS treatment failed to affect functional allosteric interactions between GABA-A receptor binding sites, as evidenced by a unchanged ability of GABA to stimulate or to inhibit [3H]flunitrazepam and [3H]TBOB binding, respectively. The findings that prolonged DHEAS treatment does not produce changes in GABA-A 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.

DHEAS; GABA-A receptor; HEK 293 cells; long-term treatment; ligand binding

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