Indoleamine-2,3-dioxygenase-1 is a molecular target for the protective activity of mood stabilizers against mania-like behavior induced by d-amphetamine

• Published in: Food and chemical toxicology Vol. 136; p. 110986
• Main Authors: Tran, Hai-Quyen, Shin, Eun-Joo, Saito, Kuniaki, Tran, The-Vinh, Phan, Dieu-Hien, Sharma, Naveen, Kim, Dae-Won, Choi, Soo Young, Jeong, Ji Hoon, Jang, Choon-Gon, Cheong, Jae Hoon, Nabeshima, Toshitaka, Kim, Hyoung-Chun
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2020
• Subjects: d-amphetamine-induced mania-like behavior; IDO-1 knockout mice; IDO-2 knockout mice; Mitochondrial stress; Mood stabilizer; Oxidative burden; DNPH; AMP; KP; VPA; DCF; d-amphetamine-induced mania-like behavior; SOD; GPx; Oxidative burden; Mitochondrial stress; DCFH-DA; MMP; Mood stabilizer; IDO; 1-MT; IDO-1 knockout mice; IDO-2 knockout mice; Li; TDO; HNE; JC-1
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2019.110986

It is recognized that d-amphetamine (AMPH)-induced hyperactivity is thought to be a valid animal model of mania. In the present study, we investigated whether a proinflammatory oxidative gene indoleamine-2,3-dioxygenase (IDO) is involved in AMPH-induced mitochondrial burden, and whether mood stabilizers (i.e., lithium and valproate) modulate IDO to protect against AMPH-induced mania-like behaviors. AMPH-induced IDO-1 expression was significantly greater than IDO-2 expression in the prefrontal cortex of wild type mice. IDO-1 expression was more pronounced in the mitochondria than in the cytosol. AMPH treatment activated intra-mitochondrial Ca2+ accumulation and mitochondrial oxidative burden, while inhibited mitochondrial membrane potential and activity of the mitochondrial complex (I > II), mitochondrial glutathione peroxidase, and superoxide dismutase, indicating that mitochondrial burden might be contributable to mania-like behaviors induced by AMPH. The behaviors were significantly attenuated by lithium, valproate, or IDO-1 knockout, but not in IDO-2 knockout mice. Lithium, valproate administration, or IDO-1 knockout significantly attenuated mitochondrial burden. Neither lithium nor valproate produced additive effects above the protective effects observed in IDO-1 KO in mice. Collectively, our results suggest that mood stabilizers attenuate AMPH-induced mania-like behaviors via attenuation of IDO-1-dependent mitochondrial stress, highlighting IDO-1 as a novel molecular target for the protective potential of mood stabilizers. [Display omitted] •AMPH significantly enhanced mitochondrial IDO-1 (but not IDO-2) expression.•IDO-1 KO attenuated AMPH-induced mitochondrial dysfunction and oxidative burden.•Anti-manic potential of mood stabilizers is comparable to that of IDO-1 KO in mice.•IDO-1 may be a novel target for anti-manic potential of mood stabilizers.