title: Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons.
abstract: Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA 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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Klas R
authors.initials: KR
authors.lastname: Linderholm
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Maximilian Tufvesson
authors.initials: MT
authors.lastname: Alm
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Larsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Olsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Michel
authors.initials: M
authors.lastname: Goiny
authors.affiliation: Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajos
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: goran.engberg@ki.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Engberg
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000637:Transaminases / Q000037:antagonists & inhibitors*
chemical_list: C583657:PF-04859989; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase
keywords: CGP-52432; Dopamine; Firing; GABA-receptor; Kynurenic acid; Kynurenine transferase; NMDA-receptor; PF-04859989; Picrotoxin; Ventral tegmental area; d-Cycloserine