Abstract

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 γ-aminobutyric acid (GABA)_A receptor function. By use of a rapid drug perfusion system, colchicine (10–1000 μM) significantly inhibited GABA currents recorded from L(tk⁻) cells stably transfected with human α1β2γ2L GABA_A receptor subunits. The inhibition was rapid and reversible, with 100 μM colchicine shifting the GABA EC₅₀ from 2.5 to 5.1 μM with no effect on currents evoked by saturating concentrations of GABA. Colchicine also significantly inhibited binding of the competitive GABA_Areceptor antagonist [³H]SR-95531. Other microtubule disrupting agents (10 μM vinblastine, 10 μg/ml nocodazole, 1 μM taxol) had no acute effects on GABA currents, nor did the inactive analog γ-lumicolchicine (100 μM). 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 GABA_A receptor function through a direct interaction with the receptor/ion channel complex.