Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine.
BACKGROUND
Cognitive deficits represent a core symptom cluster in schizophrenia (SZ) that is predictive of outcome but not effectively treated by current antipsychotics. Thus, there is a need for validated animal models for testing potential pro-cognitive drugs.


OBJECTIVE
As kynurenic acid levels are increased in prefrontal cortex (PFC) of individuals with SZ, we acutely increased brain levels of this astrocyte-derived, negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs) by administration of its bioprecursor kynurenine and measured the effects on extracellular kynurenic acid and glutamate levels in PFC and also performance in a set-shifting task.


RESULTS
Injections of kynurenine (100 mg/kg, i.p.) increased extracellular kynurenic acid (1,500%) and decreased glutamate levels (30%) in PFC. Kynurenine also produced selective deficits in set-shifting. Saline- and kynurenine-treated rats similarly acquired the compound discrimination and intra-dimensional shift (saline, 7.0 and 6.3 trials, respectively; kynurenine, 8.0 and 6.7). Both groups required more trials to acquire the initial reversal (saline, 15.3; kynurenine, 22.2). Only kynurenine-treated rats were impaired in acquiring the extra-dimensional shift (saline, 8.2; kynurenine, 21.3). These deficits were normalized by administering the α7nAChR positive allosteric modulator galantamine (3.0 mg/kg, i.p) prior to kynurenine, as trials were comparable between galantamine + kynurenine (7.8) and controls (8.2). Bilateral local perfusion of the PFC with galantamine (5.0 μM) also attenuated kynurenine-induced deficits.


CONCLUSIONS
These results validate the use of animals with elevated brain kynurenic acid levels in SZ research and support studies of drugs that normalize brain kynurenic acid levels and/or positively modulate α7nAChRs as pro-cognitive treatments for SZ.
Department of Psychology and Neuroscience, The Ohio State University, 1835 Neil Ave., Columbus, OH 43210, USA.
Kathleen S
KS
Alexander
Hui-Qiu
HQ
Wu
Robert
R
Schwarcz
John P
JP
Bruno
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D005702:Galantamine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000633:toxicity*; D008297:Male; D018697:Nootropic Agents / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D018697:Nootropic Agents; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005702:Galantamine; D007737:Kynurenine; D018698:Glutamic Acid; D007736:Kynurenic Acid