INTERACTIONS OF INDOMETHACIN WITH CENTRAL GABA SYSTEMS

Neurochemical studies showed that indomethacin is a noncompetitive inh ibitor of the mouse cortical synaptosomal uptake of [H-3]GABA with a K (i) of 0.7 mM. Indomethacin also displaced [H-3]flunitrazepam and [H-3 ]GABA binding to washed cortical membranes in a competitive manner wit h IC50 values of 0.18 and 0.55 mM, respectively. It binds to the benzo diazepine receptors with the same characteristics as an inverse agonis t and to the GABA(A) receptors as an antagonist. Behavioral studies sh owed that indomethacin dose-dependently increased the durations of los s of righting reflex induced by either diazepam or pentobarbitone, dec reased rota-rod treading times and effectively prevented generalized s eizures induced by pentylenetetrazole, bicuculline, 6,7-dimethoxy-4-et hyl-beta-carboline-3-carboxylate or maximal electroshock treatment. It is concluded that these effects of indomethacin are probably a result of GABA uptake inhibition. The present findings may explain some side effects of indomethacin on the central nervous system, such as impair ment of psychomotor functions.