engleski

The effects of prolonged exposure of recombinant GABA-A receptors in cell culture to alcohol and gabapentin

Prolonged exposure of GABA-A receptors to alcohol triggers adaptive changes often associated with the development of alcoholism. Anticonvulsant drug gabapentin, structural analogue of GABA, has shown some promise in the treatment of alcoholism and alcohol withdrawal. Despite the therapeutic efficacy of gabapentin, its precise molecular and cellular mechanisms of action are still unclear. Recent reports also suggested potential neuroprotective and antioxidant effects of gabapentin. Hence, the aim of this study was to investigate the protective action of gabapentin on the well-known neurotoxic effects of chronic alcohol consumption and withdrawal. We chronically exposed the human embryonic kidney (HEK) 293 cells, stably expressing alpha1beta2gamma2S subtype of GABA-A receptors, to alcohol (100 microM), either alone or in combination with 1 microM gabapentin. The results demonstrated that cytotoxic effect of prolonged alcohol treatment (96h) on HEK cells was reduced by alcohol withdrawal (24h) and simultaneous gabapentin treatment. Prolonged alcohol treatment induced an increase in the number of central benzodiazepine binding sites and allosteric uncoupling between GABA-A receptor binding sites, which were counteracted by alcohol withdrawal. Gabapentin did not affect the number of benzodiazepine binding sites, but restored normal functional interactions between GABA and benzodiazepine binding sites. The results suggest that long-term alcohol exposure induces changes of recombinant GABA-A receptors similar to chronic benzodiazepines, which also induce dependence. These findings also support the hypothesis of GABA-A receptor involvement in the actions of gabapentin. Further studies should investigate whether functional coupling of GABA-A receptor binding sites underlies the protective effect of gabapentin against the alcohol cytotoxicity.

alcohol; long-term treatment; withdrawal; recombinant GABA-A receptors; HEK 293 cells; gabapentin

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