Brain mechanisms of poly I:C-induced fatigue in rats

The clinical symptoms of chronic fatigue syndrome (CFS) have been shown to include disorders in the neuroendocrine, autonomic, and immune systems. On the other hand, it has been demonstrated that cytokines produced in the brain play significant roles in neural-immune interactions through their various central actions, such as activation of the hypothalamo-pituitary axis and sympathetic nervous system. We have recently developed an animal model for fatigue induced by intra-peritoneal (i.p.) injection of synthetic double-stranded RNAs, polyriboinosinic: polyribocytidylic acid (poly I:C, 3 mg/kg), in rats, and shown a decrease in the daily amounts of spontaneous running-wheel activity to about 60% of the preinjection level for more than 1 week. Simultaneously, mRNAs for interferon-α (IFN-α) and serotonin transporter (5-HTT), which is known to be induced by IFN-α, increased for more than a week following poly I:C injection in the same hypothalamic nuclei and cortex. The increased 5-HTT had a functional significance, since in vivo brain microdialysis revealed that an i.p. injection of poly I:C induced a decrease in the extracellular concentration of 5-HT in the prefrontal cortex, which was blocked by a local perfusion with the selective 5-HT re-uptake inhibitor, fluoxetine. Finally the poly I:C-induced fatigue was attenuated by 5-HT_1A receptor agonist, but not by 5-HT₂, 5-HT₃, or dopamine D3 agonists. These findings suggested that the decrease in 5-HT actions on 5-HT_1A receptors may at least partly contribute to the poly I:C-induced fatigue.