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Disturbance of rapid eye movement (REM) sleep appears early in both patients with Huntington's disease (HD) and mouse models of HD. Selective serotonin reuptake inhibitors are widely prescribed for patients with HD, and are also known to suppress REM sleep in healthy subjects. To test whether selective serotonin reuptake inhibitors can correct abnormal REM sleep and sleep-dependent brain oscillations in HD mice, we treated wild-type and symptomatic R6/2 mice acutely with vehicle and paroxetine (5, 10, and 20 mg/kg). In addition, we treated a group of R6/2 mice chronically with vehicle or paroxetine (20 mg/kg/day) for 8 weeks, with treatment starting before the onset of overt motor symptoms. During and after treatment, we recorded electroencephalo-gram/electromyogram from the mice. We found that both acute and chronic paroxetine treatment normalized REM sleep in R6/2 mice. However, only chronic paroxetine treatment prevented the emergence of abnormal low-gamma (25-45 Hz) electroencephalogram oscillations in R6/2 mice, an effect that persisted for at least 2 weeks after treatment stopped. Chronic paroxetine treatment also normalized REM sleep theta rhythm in R6/2 mice, but, interestingly, this effect was restricted to the treatment period. By contrast, acute paroxetine treatment slowed REM sleep theta rhythm in WT mice but had no effect on abnormal theta or low-gamma oscillations in R6/2 mice. Our data show that paroxetine treatment, when initiated before the onset of symptoms, corrects both REM sleep disturbances and abnormal brain oscillations, suggesting a possible mechanistic link between early disruption of REM sleep and the subsequent abnormal brain activity in HD mice.

Hippocampal rhythmic slow activity (RSA) is a well-known electrophysiological feature of exploratory behavior, spatial cognition, and rapid eye movement (REM) sleep in several mammalian species. Recently, RSA in humans during spatial navigation was reported, but systematic data regarding human REM sleep are lacking. Using mesio-temporal corticography with foramen ovale electrodes in epileptic patients, we report the presence of a 1.5-3-Hz synchronous rhythmic hippocampal oscillation seemingly specific to REM sleep. This oscillation is continuous during whole REM periods, is clearly observable by visual inspection, and appears in tonic and phasic REM sleep episodes equally. Quantitative analysis proved that this 1.5-3-Hz frequency band significantly differentiates REM sleep from waking and slow-wake sleep (SWS). No other frequency band proved to be significant or showed this high rhythmicity. Even in temporo-lateral surface recordings, although visually much less striking, the relative power of the 1.5-3-Hz frequency band differentiates REM sleep from other states with statistical significance. This could mean that the 1.5-3-Hz hippocampal RSA spreads over other cortical areas in humans as in other mammals. We suggest that this oscillation is the counterpart of the hippocampal theta of mammalian REM sleep, and that the 1.5-3-Hz delta EEG activity is a basic neurophysiological feature of human REM sleep.

These results indicate that the orexin neurons are necessary for the circadian suppression of REM sleep. Blunting of the REM sleep rhythm in Atx mice but not in orexin KO mice suggests that other signaling molecules such as dynorphin or glutamate may act in concert with orexins to suppress REM sleep during the active period.

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Our findings provide evidence that MDMA use can lead to long-term changes in regulation of circadian rhythms, motor activity and sleep generation.

1 Serotonin-2 receptor antagonists, like ritanserin, greatly enhance deep slow wave sleep (SWS-2) and low-frequency EEG power in humans and rodents. 5-HT 2A and 5-HT 2C receptors may be involved in these effects, but the role of the 5-HT 2B receptor is still unclear. 2 To investigate the role of the 5-HT 2B receptor in regulation of the sleep-wake cycle, the subtypeselective antagonist SB-215505 (0.1, 0.3 and 1.0 mg kg À1 i.p.) was administered to Sprague-Dawley rats at light onset (beginning of passive phase). EEG, EMG and motor activity were recorded during the subsequent 8 h. 3 SB-215505 dose-dependently increased wakefulness (W) at the expense of the intermediate stage of sleep, paradoxical sleep (PS) and SWS-2 in the first hour. Parallel to increased W, significantly increased motor activity was found. Spectral analysis of the EEG in W showed a dose-dependent decrease in power density in the 3-8 Hz frequency range (maximum effect at 6 Hz). In light slow wave sleep and SWS-2, the drug reduced low-frequency (o8 Hz) EEG power, suggesting decreased sleep intensity after SB-215505 treatment. In PS, the drug dose-dependently decreased EEG power solely in the theta (6-9 Hz) band, primarily affecting the peak power value (7 Hz). 4 The well-known SWS-2 enhancing effect of 5-HT 2 receptor antagonists is mediated by 5-HT 2A and/or 5-HT 2C receptors. In contrast, blockade of 5-HT 2B receptors increases motor activity and W along with decreased theta activity during W and PS. Activation of 5-HT 2B receptors may contribute to initiation of sleep and to theta generation during W and PS under physiological conditions.

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