Presynaptic kynurenate-sensitive receptors inhibit glutamate release

Kynurenic acid is a tryptophan metabolite provided with antagonist activity on ionotropic glutamate and alpha7 nicotinic acetylcholine receptors. We n oticed that in rats with a dialysis probe placed in the head of their cauda te nuclei, local administration of kynurenic acid (30-100 nM) significantly reduced glutamate output. Qualitatively and quantitatively similar effects were observed after systemic administration of kynurenine hydroxylase inhi bitors, a procedure able to increase brain kynurenate concentrations. Inter estingly, in microdialysis studies, methyllycaconitine (0.3-10 nM), a selec tive alpha7 nicotinic receptor antagonist. also reduced glutamate output. i n isolated superfused striatal synaptosomes, kynurenic acid (100 nM), but n ot methyllycaconitine, inhibited the depolarization (KCl 12.5 mM)-induced r elease of transmitter or previously taken-up [H-3]-D-aspartate. This inhibi tion was not modified by glycine, N-methyl-D-aspartate or subtype-selective kainate receptor agents, while CNQX or DNQX (10 muM), two AMPA and kainate receptor antagonists, reduced kynurenic acid effects. Low concentrations o f kynurenic acid, however, did not modify [H-3]-kainate (high and low affin ity) or [H-3]-AMPA binding to rat brain membranes. Finally, because metabot ropic glutamate (mGlu) receptors modulate transmitter release in striatal p reparations, we evaluated, with negative results, kynurenic acid (1-100 nM) effects in cells transfected with mGlu(1), mGlu(2), mGlu(4) or mGlu(5) rec eptors. In conclusion, our data show that kynurenate-induced inhibition of glutamate release is not mediated by glutamate receptors. Nicotinic acetylc holine receptors, however, may contribute to the inhibitory effects of kynu renate found in microdialysis studies, but not in those found in isolated s ynaptosomes.