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Prolonged therapy with antidepressants increases hippocampal level of kynurenic acid and expression of Kat1 and Kat2 genes

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Abstract

Background

Accumulating data suggest an important role of disturbed kynurenine pathway and altered glutamatergic transmission in the pathogenesis of depression. In here, we focused on detailed analyses of kynurenic acid (KYNA) status in vivo following single and 14-day administration of selected tricyclic antidepressant drugs (TCAs) and serotonin selective reuptake inhibitors (SSRIs) in rats.

Methods

The effect of antidepressants on serum and brain KYNA levels, as well as on the activity of kynurenine aminotransferases (KATs I and II) and expression of Kat1 and Kat2 genes mRNA was studied in three brain regions.

Results

Chronic, but not acute, application of antidepressants invariably stimulated KYNA production in hippocampus (amitriptyline, imipramine, fluoxetine and citalopram) and sporadically in cortex (amitriptyline, fluoxetine), whereas no change in KYNA level was observed in striatum. Cortical and hippocampal expression of Kat1 and Kat2 genes was increased after chronic, but not single administration of all studied antidepressants. The activity of semi-purified enzymatic proteins, KAT I and II, was not paralleling changes of Kat1 and Kat2 genes.

Conclusion

Our data indicate that prolonged administration of antidepressants targets expression of KYNA biosynthetic enzymes. Furthermore, post-translational modulation of KATs seems to play an important role in tuning of KYNA synthesis within brain structures. We suggest that consistent increase of hippocampal KYNA levels may represent hallmark of antidepressant activity. Mechanisms governing region- and drug-selective action of antidepressants require further investigations.

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Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical University in Lublin, Lublin, Poland

    Tomasz Kocki

  2. Laboratory of Cellular and Molecular Pharmacology, Department of Pharmacology and Toxicology, Medical University in Lublin, Lublin, Poland

    Ewa M. Urbańska & Renata Kloc

  3. Department of Clinical Genetics, Medical University in Lublin, Lublin, Poland

    Janusz Kocki

  4. Department of Family Medicine and Community Nursing, Chair of Oncology and Environmental Health, Faculty of Health Sciences, Medical University of Lublin, Lublin, Poland

    Katarzyna Kocka

  5. II Chair of Psychiatry and Psychiatric Rehabilitation, Medical University of Lublin, Lublin, Poland

    Marcin Olajossy

  6. Department of Clinical Neuroscience, Karolinska Institute, Section of Psychiatry, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Björn Owe-Larsson

Authors
  1. Tomasz Kocki
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  2. Ewa M. Urbańska
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  3. Janusz Kocki
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  7. Björn Owe-Larsson
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Correspondence to Ewa M. Urbańska.

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Kocki, T., Urbańska, E.M., Kocki, J. et al. Prolonged therapy with antidepressants increases hippocampal level of kynurenic acid and expression of Kat1 and Kat2 genes. Pharmacol. Rep 70, 737–745 (2018). https://doi.org/10.1016/j.pharep.2018.01.004

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  • DOI: https://doi.org/10.1016/j.pharep.2018.01.004

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