Differential effects of competitive and noncompetitive NMDA receptor antagonists on GABA turnover in the mouse brain

Abstract

The modulation of GABA-mediated neurotransmission by excitatory amino acid inputs was examined by testing the effects of competitive NMDA receptor antagonists (CPP, CGS 19755, CGP 37849 and CGP 39551) and noncompetitive antagonists (dizocilpine, PCP, ketamine, dextromethorphan and SKF 10047) on the rate of GABA synthesis and depletion, two indices of GABAergic neuronal activity. The rate of GABA synthesis in the mouse was assessed in four brain regions by the elevation in GABA levels after inhibition of GABA-T with gabaculine. The rate of GABA depletion was estimated from the decrease in GABA concentrations observed after inhibition of GAD with isoniazid. The administration of anticonvulsant doses of all competitive NMDA antagonists dose-dependently decreased the rate of GABA synthesis. With the exception of CGP 39551, the time course of effects of competitive antagonists on the rate of GABA synthesis corresponded with the time course of their anticonvulsant potencies. Unlike the competitive antagonists, the noncompetitive blockers, dizocilpine, PCP, dextromethorphan and SKF 10047 had no effect on the rate of GABA synthesis.