Actions of Xanthurenic Acid, a putative endogenous Group II metabotropic glutamate receptor agonist, on sensory transmission in the thalamus

Modulation of Hippocampal Synaptic Transmission by the Kynurenine Pathway Member Xanthurenic Acid and Other VGLUT Inhibitors

“…In the CA1 region, the actions of XA were more complex and, in addition to the depression of synaptic transmission, we observed alterations in the fEPSP waveform consistent with increases in excitability. This observation concurs with previous reports that XA may be proconvulsant (Lapin, 1978a, b) and that XA reduces sensory inhibition in the thalamus (Copeland et al, 2013).…”

“…We tested the possibility that XA was a PAM, but saw no evidence of such an action. Similarly, we previously reported that XA modulates sensory processing in the rat thalamus in vivo, but the PAM LY487379 was found to not potentiate this effect (Copeland et al, 2013), whereas the effects of a Group II agonist were enhanced by the PAM (Copeland et al, 2012). In the CA1 region, consistent with previous reports (Gereau and Conn, 1995), application of LY354740 had no effect on synaptic transmission at the Schaffer collateral-CA1 synapse, whereas XA produced clear effects.…”

“…A body of evidence suggests that XA may serve a neuromodulatory function, including wide-spread, heterogeneous CNS levels; accumulation in synaptic terminals; release of XA upon electrical stimulation (Gobaille et al, 2008); intracerebrocentricular XA administration inducing seizures (Lapin, 1978b) and intraperitoneal administration in rats being antinociceptive (Heyliger et al, 1998;Fazio et al, 2012). A number of factors suggest that XA might have a role in psychiatric disorders, such as schizophrenia: first, some early reports suggested altered levels of XA and tryptophan metabolism in schizophrenic patients (Price et al, 1959;Benassi et al, 1961); second, we have found that XA modulates sensory inhibition in the thalamus in vivo (Copeland et al, 2013), a process that may be of importance in schizophrenia (Pinault, 2011); third, the reported molecular targets of XA are believed to be VGLUTs (Bartlett et al, 1998;Carrigan et al, 2002) and, recently, preliminary evidence suggested that XA may also modulate Group II metabotropic glutamate (mGlu) receptor function (Fazio et al, 2012;Mauro et al, 2010). Altered activity of both VGLUT and Group II mGlu receptors has been linked to schizophrenia (Fell et al, 2011;Gonzalez-Maeso et al, 2008;Eastwood and Harrison, 2005;Varea et al, 2012).These strands of evidence are all suggestive that maladaptation of XA metabolism may be involved in the pathophysiology of schizophrenia; therefore, we thought it is important to further explore the potential of XA to modulate neuronal function.…”

Transport of Xanthurenic Acid by Rat/Human Organic Anion Transporters OAT1 and OAT3

“…Although xanthurenic acid was represented to interact with several kinds of receptors in the brain, further research is required to clear what is acquired from the interaction. 4,5) Cain et al reported that 8-O--D-glucoside and 8-O-sulfate of xanthurenic acid caused natriuresis in rats. 28) Sulfation of xanthurenic acid occurred in various tissues including the liver, stomach, jejunum, colon, and kidney, and sulfotransferase SULT1C2 was exhibited to be predominantly expressed in the proximal tubule, where OAT1 and OAT3 work.…”

“…In contrast with kynurenic acid, action of xanthurenic acid remains to be elucidated, but lately xanthurenic acid has been reported to interact with the Group II metabotropic glutamate receptor and G-protein-coupled receptors in the brain. 4,5) Thus, it too might influence brain function.…”