Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons

NEUROPHARMACOLOGY

卷:102

Article

Linderholm, Klas R.¹  Alm, Maximilian Tufvesson¹  Larsson, Markus K.¹  Olsson, Sara K.¹  Goiny, Michel¹  Hajos, Mihaly²  Erhardt, Sophie¹  Engberg, Goran¹ 

[1] Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden

[2] Yale Univ, Sch Med, Dept Comparat Med, New Haven, CT USA

关键词: Kynurenic acid;    Dopamine;    Ventral tegmental area;    Firing;    Kynurenine transferase;    GABA-receptor;    NMDA-receptor;    PF-04859989;    D-Cycloserine;    CGP-52432;    Picrotoxin;   

DOI  :  10.1016/j.neuropharm.2015.10.028

来源: Elsevier

【 摘 要 】

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain MYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4-6 after administration. Pretreatment with D-cycloserine (30 mg/kg) or CGP-52432 (10 mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain. (c) 2015 The Authors. Published by Elsevier Ltd.

【 授权许可】

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