NQO1 regulates pharmaco-behavioral effects of d-amphetamine in striatal dopaminergic system in mice.
The NAD(P)H:quinone oxidoreductase 1 (NQO1) gene encodes a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones to hydroquinones. A polymorphic form of NQO1 is associated with mood disorders such as schizophrenia. However, the role of NQO1 in dopaminergic system has not yet been elucidated. To determine the role of NQO1 in the dopaminergic system, we investigated pharmaco-behavioral effects of d-amphetamine using NQO1-deficienct mice. According to our comparative study involving NQO1+/+ and NQO1-/- mice, NQO1 deficiency increased d-amphetamine-induced psychomotor activity and psychological dependency compared to wild-type mice. Basal and d-amphetamine-induced dopamine levels were also enhanced by NQO1 deficiency. In NQO1-/- mice, neural activation induced by d-amphetamine was higher in dorsolateral striatum, but not in dorsomedial and ventral striata. Although protein level of CaMKIIα, which is a key player in amphetamine-induced dopamine efflux, was decreased in striata of NQO1-/- mice, phosphorylation of CaMKIIα was markedly enhanced in NQO1-/- mice compared to wild-type mice. Interestingly, experiments with pharmacological antagonist showed that D2 antagonist-induced suppression of locomotion required activation of NQO1. Moreover, the rewarding effect in response to D1 agonist was increased by NQO1 deficiency. These results suggest that striatal NQO1 is of considerable interest to understand the mechanism of dopaminergic regulation of psychiatric disorders.
['Go|Jun|J|', 'Ryu|Young-Kyoung|YK|', 'Park|Hye-Yeon|HY|', 'Choi|Dong-Hee|DH|', 'Choi|Young-Keun|YK|', 'Hwang|Dae Youn|DY|', 'Lee|Chul-Ho|CH|', 'Kim|Kyoung-Shim|KS|']
D000818:Animals D003342:Corpus Striatum D003913:Dextroamphetamine D004298:Dopamine D065127:Dopamine D2 Receptor Antagonists D008124:Locomotion D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D016660:NAD(P)H Dehydrogenase (Quinone) D017447:Receptors, Dopamine D1 D017448:Receptors, Dopamine D2
d-amphetamine Dopamine Calcium/calmodulin-dependent protein kinase type II alpha Dopamine receptor NAD(P)H quinone Oxidoreductase 1