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Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine

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Abstract

Rationale

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.

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Acknowledgments

The authors’ research was supported by a grant from the National Institutes of Health (MH083729) to JPB and RS.

Disclosures/conflicts of interest

During the past 3 years, RS has received research support from Mitsubishi-Tanabe (Yokohama, Japan) and Bristol-Myers-Squibb (Wallingford, CT, USA) and served as a consultant to Merck (West Point, PA, USA). The other authors declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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  1. Department of Psychology and Neuroscience, The Ohio State University, 1835 Neil Ave., Columbus, OH, 43210, USA

    Kathleen S. Alexander & John P. Bruno

  2. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21228, USA

    Hui-Qiu Wu & Robert Schwarcz

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  1. Kathleen S. Alexander
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Correspondence to John P. Bruno.

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Alexander, K.S., Wu, HQ., Schwarcz, R. et al. Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine. Psychopharmacology 220, 627–637 (2012). https://doi.org/10.1007/s00213-011-2539-2

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