Colchicine is an alkaloid that is used clinically in the treatment of arthritic gout. This potent microtubule disrupting agent has also been used extensively as an experimental tool in studies characterizing the role of the cytoskeleton in a variety of cellular processes. Colchicine has also been used as a selective neurotoxin and in animal models of Alzheimer's disease and epilepsy. Although the mechanism(s) mediating the neurotoxic actions of colchicine have not been established, most studies have attributed these effects to its microtubule depolymerizing actions. Here we report another central nervous system action of colchicine, competitive antagonism of gamma-aminobutyric acid (GABA)A receptor function. By use of a rapid drug perfusion system, colchicine (10-1000 microM) significantly inhibited GABA currents recorded from L(tk-) cells stably transfected with human alpha 1 beta 2 gamma 2L GABAA receptor subunits. The inhibition was rapid and reversible, with 100 microM colchicine shifting the GABA EC50 from 2.5 to 5.1 microM with no effect on currents evoked by saturating concentrations of GABA. Colchicine also significantly inhibited binding of the competitive GABAA receptor antagonist [3H]SR-95531. Other microtubule disrupting agents (10 microM vinblastine, 10 micrograms/ml nocodazole, 1 microM taxol) had no acute effects on GABA currents, nor did the inactive analog gamma-lumicolchicine (100 microM). Moreover, pretreating cells with colchicine, vinblastine, nocodazole or taxol for 1 to 4 hr did not occlude the acute inhibitory action of colchicine. We conclude that, in addition to its well characterized effects on microtubule assembly, colchicine can also inhibit GABAA receptor function through a direct interaction with the receptor/ion channel complex.
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