COLCHICINE IS A COMPETITIVE ANTAGONIST AT HUMAN RECOMBINANT GAMMA-AMINOBUTYRIC ACID(A) RECEPTORS

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 th e role of the cytoskeleton in a variety of cellular processes. Colchic ine has also been used as a selective neurotoxin and in animal models of Alzheimer's disease and epilepsy. Although the mechanism(s) mediati ng the neurotoxic actions of colchicine have not been established, mos t studies have attributed these effects to its microtubule depolymeriz ing actions. Here we report another central nervous system action of c olchicine, competitive antagonism of gamma-aminobutyric acid (GABA)(A) receptor function. By use of a rapid drug perfusion system, colchicin e (10-1000 mu M) significantly inhibited GABA currents recorded from L (tk(-)) cells stably transfected with human alpha 1 beta 2 gamma 2L GA BA(A) receptor subunits. The inhibition was rapid and reversible, with 100 mu M colchicine shifting the GABA EC50 from 2.5 to 5.1 mu M with no effect on currents evoked by saturating concentrations of GABA. Col chicine also significantly inhibited binding of the competitive GABA(A ) receptor antagonist [H-3]SR-95531. Other microtubule disrupting agen ts (10 mu M vinblastine, 10 mu g/ml nocodazole, 1 mu M taxol) had no a cute effects on GABA currents, nor did the inactive analog gamma-lumic olchicine (100 mu M). Moreover, pretreating cells with colchicine, vin blastine, 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 als o inhibit GABA(A) receptor function through a direct interaction with the receptor/ion channel complex.