Title

 

Authors

S. Beggiato¹, L. Ferraro¹, S. Tanganelli¹, M.C. Tomasini¹, T.Antonelli¹, K. Fuxe², H.Q. Wu³ and R. Schwarcz^3
 
1Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara (Italy), ²Department of Neuroscience, Karolinska Institute, Stockholm (Sweden), and³Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland (USA

 

Abstract

Kynurenic acid (KYNA), a product of the kynurenine pathway of tryptophan metabolism, is an astrocyte-derived, non-competitive antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR; Hilmas et al., 2001) and, at higher concentrations, inhibits ionotropic glutamate receptors competitively. In the striatum, exogenous or endogenously formed KYNA reduces extracellular glutamate levels by blocking presynaptic α7nAChRs on glutamatergic nerve terminals. This effect, in turn, decreases extracellular dopamine levels (Carpenedo et al., 2001; Rassoulpour et al., 2005). Using microdialysis in unanesthetized, adult rats, we now studied the effects of KYNA (30, 100, 300 and 1000 nM) on extracellular glutamate and GABA in the striatum. The two amino acids were always determined in the same microdialysate. Applied for 2 hrs by reverse dialysis, KYNA concentration-dependently reduced both glutamate and GABA levels, with 300 nM KYNA causing a nadir of approximately 60% of baseline concentrations. No further reductions were observed when KYNA was applied at 1000 nM. In all cases, glutamate and GABA gradually reverted to control levels after the withdrawal of KYNA. The effects of KYNA were prevented by the co-application of galantamine (5 μM), a positive allosteric modulator that binds at a site of the α7nAChR that is very similar to that targeted by KYNA. Notably, galantamine raised both glutamate and GABA levels on its own (by ~35% of baseline levels). In a separate set of experiments, endogenous KYNA formation was inhibited by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA;1 mM), a specific inhibitor of kynurenine aminotransferase II, KYNA’s major biosynthetic enzyme in the brain (Pellicciari et al., 2006). ESBA not only reduced extracellular KYNA (nadir: ~65% of baseline levels) but reversibly increased glutamate and GABA levels, reaching a peak of ~160% of baseline levels for both amino acids. Co-infusion of 100 nM KYNA abolished the effect of ESBA on extracellular glutamate and GABA, confirming the specificity of the ESBA effect. Moreover, co-infusion of the sodium channel blocker tetrodotoxin (2 µM) significantly attenuated the ESBA-induced increase in extracellular glutamate and GABA. Taken together, these results indicate that fluctuations in the endogenous formation of KYNA bi-directionally influence extracellular glutamate and GABA levels in the rat striatum. This tonic regulation, which appears to be mediated by α7nAChRs, suggests a role of astrocyte-derived KYNA in the control of glutamatergic and, possibly subsequently, GABAergic neurotransmission. These functional links, which are currently studied in greater detail in our laboratories, may be relevant for a number of physiological and pathological processes involving the basal ganglia.

 

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Hilmas et al. (2001). J. Neurosci. 21:7463-73.
Pellicciari et al. (2006). ChemMedChem. 1:528-31.
Rassoulpour et al. (2005). J. Neurochem. 93:762-5.