Sleep disturbance associated with an enhanced orexinergic system induced by chronic treatment with paroxetine and milnacipran

Abstract

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.

Predicting Drug–Target Interactions Using Probabilistic Matrix Factorization

“…44 We also note that chronic treatment with paroxetine has been recently reported to increase the mRNA levels of histamine receptor H 1 , indicating an association between paroxetine and Histamine receptor H1. 45 Although paroxetine is a potent serotonin reuptake inhibitor, its weight gain side effect has been attributed to its medication action on histamine receptors. 46 …”

“…44 We also note that chronic treatment with paroxetine has been recently reported to increase the mRNA levels of histamine receptor H 1 , indicating an association between paroxetine and Histamine receptor H1. 45 Although paroxetine is a potent serotonin reuptake inhibitor, its weight gain side effect has been attributed to its medication action on histamine receptors. 46 Many others (indicated as "indirect") are interactions known to occur either with subtypes of the listed targets or proteins implicated in the same phenotype (e.g., citalopram induces norepinephrine receptor hypoactivity, 47 which may relate to norepinephrine transport by NET).…”

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia

“…Adults (over 18 years) having a clinical diagnosis of fibromyalgia by any published, recognized and standardized criteria (Smythe 1981; Wolfe 1990; Wolfe 2010; Wolfe 2011b, Yunus 1981; Yunus 1982; Yunus 1984). …”

The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study

“…Both of these neurotransmitters also contribute to wakefulness. 35 The current study had several limitations that hindered our ability to draw any firm conclusions. Given the small sample size and the resultant expanded variability, virtually all or most of the subjects would have had to show improvements in pain in order to demonstrate a significant effect on sleep (see endnote).…”

“…34 Whereas, both monoamines contribute to pain and sleep modulation, the higher norephinephrine reuptake activity may account for the lack of sedation seen in these subjects. 29,35 In addition, milnacipran has been shown to increase orexinergic transmission in the hypothalamus and histaminic transmission in the frontal cortex. Both of these neurotransmitters also contribute to wakefulness.…”