PICOLINIC-ACID MODULATES KAINIC ACID-EVOKED GLUTAMATE RELEASE FROM THE STRIATUM IN-VITRO

Since picolinic acid, a tryptophan metabolite yielded by the kynurenin e pathway, selectively attenuates quinolinic and kainic acid excitotox icity that is dependent on the presence of a glutamatergic afferent in put, it was hypothesized that this agent may inhibit the presynaptic r elease of glutamate. Using superfused rat striatal slices, this study examined the potential of picolinic acid, and related pyridine monocar boxylic acids, to modify kainic acid-induced glutamate release. Kainic acid (0.25, 0.5 and 1.0 mM) stimulated the release of glutamate, an e ffect which was calcium dependent and was attenuated in the presence o f the kainate/AMPA receptor antagonist, 6,7-dinitroquinoxalene-2,3-dio ne (500 muM). Picolinic acid significantly decreased glutamic acid rel ease evoked by exposure of striatal slices to 1 mM kainate in the pres ence of calcium. The inhibitory action of picolinic acid on kainate-in duced release was also shared by nicotinic and isonicotinic acid. In t he absence of external calcium, kainic acid-induced glutamate release was significantly reduced by approximately 65%. Under this condition, picolinic acid (100 muM) failed to influence kainic acid-induced relea se. Picolinic acid (100 muM) itself increased glutamate release by 35% over basal release. While the ability of picolinic acid to inhibit ex citotoxin-induced release supports the notion that it may act presynap tically to modify excitotoxicity, lack of structural specificity in it s action tends to cast doubt on this mechanism of action.