title: A systemically-available kynurenine aminotransferase II (KAT II) inhibitor restores nicotine-evoked glutamatergic activity in the cortex of rats.
abstract: Kynurenic acid (KYNA) is a tryptophan metabolite that acts in the brain as an endogenous antagonist at multiple receptors, including glutamate and α7 nicotinic acetylcholine receptors. Increased levels of KYNA have been demonstrated in the brain of patients with a range of neurocognitive disorders, including schizophrenia, and are hypothesized to contribute to cognitive symptoms. Reducing KYNA levels by administering inhibitors of enzymes of the kynurenine pathway, particularly kynurenine aminotransferase II (KAT II), has been proposed as a treatment for such cognitive impairments. Here we report that administration of a systemically available KAT II inhibitor, PF-04859989, restores glutamate release events ("transients") evoked by pressure ejections of nicotine into the prefrontal cortex of rats exhibiting elevated KYNA levels. Nicotine-evoked glutamatergic transients can be reliably evoked and recorded after repeated pressure ejections of nicotine over 4-5 h. Systemic administration of l-kynurenine (100 mg/kg; i.p.) significantly increased frontal cortical KYNA levels and greatly attenuated the amplitude of nicotine-evoked glutamatergic transients. Systemic administration of PF-04859989 30 min prior to administration of l-kynurenine, but not when administered 30 min after l-kynurenine, restored glutamatergic transients recorded up to 75 min after the administration of the KAT II inhibitor. Furthermore, the KAT II inhibitor significantly reversed l-kynurenine-induced elevations of brain KYNA levels. The KAT II inhibitor did not affect nicotine-evoked glutamatergic transients in rats not pre-treated with l-kynurenine. Because PF-04859989 restores evoked glutamate signaling it therefore is a promising therapeutic compound for benefiting the cognitive symptoms of schizophrenia and other disorders associated with elevated brain KYNA levels.
authors.affiliation: Department of Psychology & Neuroscience Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Ajeesh
authors.initials: A
authors.lastname: Koshy Cherian
authors.affiliation: Department of Psychology & Neuroscience Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Gritton
authors.affiliation: Neuroscience Research Unit, Pfizer Inc., Boston, MA, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Neuroscience Research Unit, Pfizer Inc., Boston, MA, USA.
authors.forename: Damon
authors.initials: D
authors.lastname: Young
authors.affiliation: Neuroscience Research Unit, Pfizer Inc., Boston, MA, USA.
authors.forename: Rouba
authors.initials: R
authors.lastname: Kozak
authors.affiliation: Department of Psychology & Neuroscience Program, University of Michigan, Ann Arbor, MI, USA. Electronic address: msarter@umich.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Sarter
mesh_terms: D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017551:Microdialysis; D008839:Microelectrodes; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D004791:Enzyme Inhibitors; D018722:Nicotinic Agonists; C583657:PF-04859989; D011720:Pyrazoles; D007737:Kynurenine; D018698:Glutamic Acid; D011189:Potassium Chloride; D009538:Nicotine; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid
keywords: Cognition; KAT II; Kynurenic acid; PF-04859989; Schizophrenia; l-Kynurenine