Recent reports have shown that acute or chronic treatment with selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI) causes unpleasant side effects in patients. In the present study, through the use of electroencephalography (EEG) and electromyography (EMG), we found that chronic treatment with the SSRI paroxetine or the SNRI milnacipran significantly induced sleep disturbance, which was characterized by an increase in the total wake time and decreased total nonrapid eye movement (NREM) sleep. Furthermore, RT-PCR analysis demonstrated that chronic treatment with paroxetine or milnacipran significantly increased the mRNA levels of orexin 1 receptor and orexin 2 receptor in the hypothalamus and of histamine 1 receptor and histidine decarboxylase in the frontal cortex of mice. The present findings suggest that chronic treatment with either paroxetine or milnacipran causes sleep disturbance associated with an increase in orexinergic transmission in the hypothalamus and histaminergic transmission in the frontal cortex. Although further studies are needed, these imbalances in the orexinergic and histaminergic systems may be, at least in part, responsible for the pathogenesis of sleep disturbance induced by chronic treatment with SSRI or SNRI in rodents.
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