Importance of kynurenine 3-monooxygenase for spontaneous firing and pharmacological responses of midbrain dopamine neurons: L Check for Relevance for schizophrenia

NEUROPHARMACOLOGY

卷:138

Article

Tufvesson-Alm, Maximilian¹  Schwieler, Lilly¹  Schwarcz, Robert²  Goiny, Michel¹  Erhardt, Sophie¹  Engberg, Goran¹ 

[1] Karolinska Inst, Dept Physiol & Pharmacol, Biomed 5C,Nanna Svartz Vag 2, S-17177 Stockholm, Sweden

[2] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA

关键词: Kynurenic acid;    Electrophysiology;    Dopamine;    Schizophrenia;    NMDA receptor;   

DOI  :  10.1016/j.neuropharm.2018.06.003

来源: Elsevier

【 摘 要 】

Kynurenine 3-monooxygenase (KMO) is an essential enzyme of the kynurenine pathway, converting kynurenine into 3-hydroxykynurenine. Inhibition of KMO increases kynurenine, resulting in elevated levels of kynurenic acid (KYNA), an endogenous N-methyl-D-aspartate and alpha*7-nicotinic receptor antagonist. The concentration of KYNA is elevated in the brain of patients with schizophrenia, possibly as a result of a reduced KMO activity. In the present study, using in vivo single cell recording techniques, we investigated the electrophysiological characteristics of ventral tegmental area dopamine (VTA DA) neurons and their response to antipsychotic drugs in a KMO knock-out (K/O) mouse model. KMO K/O mice exhibited a marked increase in spontaneous VTA DA neuron activity as compared to wild-type (WT) mice. Furthermore, VTA DA neurons showed clear-cut, yet qualitatively opposite, responses to the antipsychotic drugs haloperidol and clozapine in the two genotypes. The anti-inflammatory drug parecoxib successfully lowered the firing activity of VTA DA neurons in KMO K/O, but not in WT mice. Minocycline, an antibiotic and anti-inflammatory drug, produced no effect in this regard. Taken together, the present data further support the usefulness of KMO K/O mice for studying distinct aspects of the pathophysiology and pharmacological treatment of psychiatric disorders such as schizophrenia. (C) 2018 Published by Elsevier Ltd.

【 授权许可】

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