The fatigue animal model made by water-immersion of rats for 5 days has been reported to show a decrease in glucose uptake and insufficient serotonin and dopamine turnover in the central nervous system, and changes in amino acid levels in the plasma and organs. In the same animal model, we also found that metabolites of the TCA cycle in organs show characteristic changes indicating decreased activity of aconitase, an enzyme converting citrate to isocitrate via cis-aconitate in mitochondria. In this study, we produced a new fatigue model in rats based on the suppression of aconitase activity by administration of monofluoroacetate (an aconitase inhibitor, MFA), and investigated the animal behavior and the mechanism.
Monofluoroacetate (1.0 mg/kg) was orally administered to male SD rats. MFA administration markedly decreased spontaneous activity in rats, and the activity recovered to the level before the MFA administration within 4 days. Although the muscle strength was also declined, it showed a faster recovery within 24 hours. Next, we measured tissue ATP contents in the liver, muscle, blood cells (erythrocytes and leukocytes), and brain. These tissues except for the brain showed the decrease in ATP contents by the MFA administration and the faster recovery within 24 hours. The brain, however, showed the delayed recovery for more than 24 hours after the reduction of ATP content. Recently, we have reported that neuroinflammation in the brain induced a decrease in spontaneous activity in a viral infection model of rats. In the present study, we also confirmed upregulated expressions of proinflammatory cytokines in the brain. These observations indicated that persistent reduction in brain energy metabolism induced neuroinflammation resulting in the suppression of spontaneous activity in rats.

This study was partly supported by drug discovery project "TaNeDS" (Daiichi-Sankyo)