Involvement of kynurenine 3-monooxygenase in the vulnerability to the PCP-induced behavioral abnormalities

[Speaker] Hisayoshi Kubota:1
[Co-author] Akihiro Mouri:1,4, Kazuo Kunisawa:2, Moe Niijima:1, Tomoaki Teshigawara:3, Mami Hirakawa:1, Yuko Mori:1, Yasuko Yamamoto:3, Toshitaka Nabeshima:2,4, Kuniaki Saito:3,4
1:Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Science, Japan, 2:Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science, Japan, 3:Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Science, Japan, 4:Japanese Drug Organization of Appropriate Use and Research, Japan

Backgrounds: The tryptophan-kynurenine pathway generates several neuroactive compounds such as kynurenic acid (KA). KA is endogenous antagonist for N-methyl-D-aspartate (NMDA) and 7 nicotinic receptors and might contribute to the pathophysiology of schizophrenia. Kynurenine 3-monooxygenase (KMO) is a rate-limiting enzyme at the branching point of the kynurenine pathway converting kynurenine to 3-hydroxykynurenine. Formation of KA is indirectly regulated by the activity. However, the contribution of KMO in the vulnerability to schizophrenia has not investigated.
Methods: C57BL/6N KMO knockout mice and their wild-type littermates were administered acutely phencyclidine (PCP) and measured locomotor activity and prepulse inhibition.
Results: Acute administration of PCP to the wild-type mice at the dose of 10 but not 5 mg/kg resulted in an increase in locomotor activity and sensory gating functioned deficit in prepulse inhibition test. When KMO knockout mice were administrated PCP, these behavioral changes were observed even at the dose of 5 mg/kg. There is no difference in their locomotor activity and sensory gating function between KMO knockout and wild-type mice administrated saline.
Conclusion: KMO knockout mice is vulnerable to the PCP-induced behavioral abnormalities.

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