Kynurenic acid, by targeting 7 nicotinic acetylcholine receptors, modulates extracellular GABA levels in the rat striatum in vivo

Kynurenic acid (KYNA) is an astrocyte-derived non-competitive antagonist of the 7 nicotinic acetylcholine receptor (7nAChR) and inhibits the NMDA receptor (NMDAR) competitively. The main aim of the present study was to examine the possible effects of KYNA (30 1000nm), applied locally by reverse dialysis for 2h, on extracellular GABA levels in the rat striatum. KYNA concentration-dependently reduced GABA levels, with 300nm KYNA causing a maximal reduction to similar to 60% of baseline concentrations. The effect of KYNA (100nm) was prevented by co-application of galantamine (5m), an agonist at a site of the 7nAChR that is very similar to that targeted by KYNA. Infusion of 7-chlorokynurenic acid (100nm), an NMDAR antagonist acting selectively at the glycineB site of the receptor, affected neither basal GABA levels nor the KYNA-induced reduction in GABA. Inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 1mm) increased extracellular GABA levels, reaching a peak of 156% of baseline levels after 1h. Co-infusion of 100nm KYNA abolished the effect of ESBA. Qualitatively and quantitatively similar, bi-directional effects of KYNA on extracellular glutamate were observed in the same microdialysis samples. Taken together, the present findings suggest that fluctuations in endogenous KYNA levels, by modulating 7nAChR function, control extracellular GABA levels in the rat striatum. This effect may be relevant for a number of physiological and pathological processes involving the basal ganglia.