Vol. 284, Issue 1, 95-102, 1998

Colchicine Is a Competitive Antagonist at Human Recombinant -Aminobutyric Acid_A Receptors¹

J. L. Weiner, A. V. Buhler, V. J. Whatley, R. A. Harris and T. V. Dunwiddie

Department of Pharmacology (J.L.W., A.V.B., V.J.W., R.A.H., T.V.D.) and Program in Neuroscience (R.A.H., T.V.D.), University of Colorado Health Sciences Center, Denver, Colorado, and Veterans Administration Medical Center (R.A.H., T.V.D.), Denver, Colorado

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 -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 122L 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_A receptor 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 -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.