Presynaptic kynurenate‐sensitive receptors inhibit glutamate release

Abstract

Kynurenic acid is a tryptophan metabolite provided with antagonist activity on ionotropic glutamate and alpha7 nicotinic acetylcholine receptors. We noticed that in rats with a dialysis probe placed in the head of their caudate 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 inhibitors, a procedure able to increase brain kynurenate concentrations. Interestingly, in microdialysis studies, methyllycaconitine (0.3-10 nM), a selective alpha7 nicotinic receptor antagonist, also reduced glutamate output. In isolated superfused striatal synaptosomes, kynurenic acid (100 nM), but not methyllycaconitine, inhibited the depolarization (KCl 12.5 mM)-induced release of transmitter or previously taken-up [3H]-D-aspartate. This inhibition was not modified by glycine, N-methyl-D-aspartate or subtype-selective kainate receptor agents, while CNQX or DNQX (10 microM), two AMPA and kainate receptor antagonists, reduced kynurenic acid effects. Low concentrations of kynurenic acid, however, did not modify [3H]-kainate (high and low affinity) or [3H]-AMPA binding to rat brain membranes. Finally, because metabotropic glutamate (mGlu) receptors modulate transmitter release in striatal preparations, we evaluated, with negative results, kynurenic acid (1-100 nM) effects in cells transfected with mGlu1, mGlu2, mGlu4 or mGlu5 receptors. In conclusion, our data show that kynurenate-induced inhibition of glutamate release is not mediated by glutamate receptors. Nicotinic acetylcholine receptors, however, may contribute to the inhibitory effects of kynurenate found in microdialysis studies, but not in those found in isolated synaptosomes.

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

“…These results, taken together, demonstrate that up-and downregulation of endogenous KYNA in the brain acutely modulate hippocampal chemistry and function in vivo. Our findings confirm and extend reports of similar glutamate changes following KYNA manipulations in other forebrain regions (Carpenedo et al, 2001;Konradsson-Geuken et al, 2009;Wu et al, 2010), and are also in line with experiments showing cognitive impairments following systemic administration of kynurenine, the immediate bioprecursor of KYNA (Chess and Bucci, 2006;Chess et al, 2007;Erhardt et al, 2004;Shepard et al, 2003). Most importantly, the present data provide the first demonstration that the cognitive improvement seen in animals with genetic, that is, chronic, elimination of KAT-II (Potter et al, 2010) can be duplicated by acute, specific KAT-II inhibition.…”

“…Microdialysis studies in the striatum and the prefrontal cortex of awake rats showed that exogenous application of KYNA in the mid-nanomolar range, that is, 2-5 times endogenous levels, reduces the extracellular concentrations of dopamine and glutamate (Amori et al, 2009;Carpenedo et al, 2001;Moroni et al, 2005;Rassoulpour et al, 2005;Wu et al, 2010). Moreover, in the prefrontal cortex, nanomolar KYNA significantly decreases the amphetamine-induced stimulation of acetylcholine release (Zmarowski et al, 2009).…”

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

“…The fact that the affinity of KYNA to these two Ca 2ϩ -permeable receptors is in the range of KYNA levels in the human brain and reasonably close to the (lower) KYNA content of the rodent brain suggests a physiological function in glutamatergic and cholinergic neurotransmission. Direct support for such a role has been provided, for example, by in vivo studies in the rat striatum where a reduction in KYNA levels enhances vulnerability to an excitotoxic insult (Poeggeler et al, 1998) and, conversely, modest elevations of KYNA inhibit glutamate release (Carpenedo et al, 2001). …”

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

“…Inhibition of these receptors by KYNA reduces extracellular glutamate levels (Carpenedo et al, 2001;Rassoulpour et al, 2005;Grilli et al, 2006). Preliminary evidence indicates that reductions in KYNA, conversely, enhance glutamatergic function by disinhibiting α7nAChRs (H.-Q.…”

“…These glia-derived signals or "gliotransmitters" include, among others, D-serine (Schell, 2004;Nishikawa, 2005;Martineau et al, 2006) and the tryptophan metabolite kynurenic acid (KYNA; Kiss et al, 2003). The latter compound is especially interesting, because it not only inhibits the NMDA receptor directly by acting at the glycine co-agonist ("glycine B ") site (Kessler et al, 1989;Parsons et al, 1997) but also decreases extracellular glutamate levels by blocking presynaptic α7 nicotinic receptors (α7nAChRs) situated on glutamatergic nerve endings (Carpenedo et al, 2001;Rassoulpour et al, 2005). KYNA is therefore increasingly viewed as an important endogenous modulator of physiological and pathological events associated with glutamatergic neurotransmission (Schwarcz, 2004;Coyle, 2006).…”