Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions.
l-Tryptophan (TRP) is metabolized via serotonin and kynurenine pathways (KP). Several studies have demonstrated that abnormality of both pathways is involved in the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the KP, has been suggested to play major roles in physiological and pathological events mediated by bioactive kynurenine metabolites. In this study, we investigated the role of KMO in the emotional and cognitive functions by using KMO knockout (KO) mice. We measured contents of TRP and monoamines and their metabolites in the serum and hippocampus of KMO KO mice. Further, we investigated whether antidepressants improved the depressive-like behaviors in KMO KO mice. KMO KO mice showed depressive-like behaviors such as decreased sucrose preference and increased immobility in the forced swimming test and high anxiety by decreased time spent in the center area of open field. But, there was no difference in spontaneous alternation in Y-maze test, counts of rearing or locomotor activity. Higher contents of TRP metabolites such as kynurenine (KYN), kynurenic acid (KA), anthranilic acid (AA), and 3-hydroxykynurenine (3-HK) in the serum and hippocampus and decreased serotonin turnover and higher content of normetanephrine (NM) in the hippocampus were observed in the KMO KO mice. Although both antidepressant attenuated increase of immobility, sertraline but not imipramine improved decrease of sucrose preference in the KMO KO mice. These findings suggested that KMO KO mice show antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions via abnormality of kynurenine metabolism with good validities as MDD model.
Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Tomoyuki
T
Tashiro
Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan; Organization for Research Initiatives and Development, Doshisha University, Kyoto 610-0394, Japan.
Yuki
Y
Murakami
Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi 470-1192, Japan; Japanese Drug Organization of Appropriate Use and Research, Aichi 468-0069, Japan.
Akihiro
A
Mouri
Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan; Lab of Nano-Bio Probe, Quantitative Biology Center (QBiC), RIKEN, Osaka 565-0874, Japan.
Yukio
Y
Imamura
Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi 470-1192, Japan; Japanese Drug Organization of Appropriate Use and Research, Aichi 468-0069, Japan; Aino University, Osaka, Ibaragi 567-0012, Japan.
Toshitaka
T
Nabeshima
Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi 470-1192, Japan.
Yasuko
Y
Yamamoto
Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan; Japanese Drug Organization of Appropriate Use and Research, Aichi 468-0069, Japan; Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi 470-1192, Japan. Electronic address: saitok@fujita-hu.ac.jp.
Kuniaki
K
Saito
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D015306:Biogenic Monoamines / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005518:Food Preferences / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000627:therapeutic use; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase / Q000172:deficiency* / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020280:Sertraline / Q000627:therapeutic use; D013395:Sucrose / Q000008:administration & dosage / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D014364:Tryptophan / Q000097:blood
D000928:Antidepressive Agents; D015306:Biogenic Monoamines; C005045:3-hydroxykynurenine; D007737:Kynurenine; D013395:Sucrose; D014364:Tryptophan; D050601:Kynurenine 3-Monooxygenase; D007099:Imipramine; D020280:Sertraline
Animal model; Kynurenine 3-monooxygenase; Kynurenine pathways; Major depressive disorder; Monoamines pathway