NREM sleep

Sleep is generally considered to consist of two substates, Rapid Eye Movement (REM) and non-Rapid Eye Movement (NREM) sleep, which alternate to form a cycle lasting 90 min in man (Fig. 1). REM and... 

Electroencephalographic (EEG), electro-oculographic (EOG) and electromyelographic (EMG) feature characteristic of the stages of sleep (NREM stages 1-4 and REM) and wake. The distinctions between REM and NREM sleep are dramatic and qualitative, including differences in EEG and EOG patterns, changes in heart... 

Generic term usually applied to the deeper stages of NREM sleep (stages 3 and 4), so called because of the high proportion of slow wave activity (SWA). 

Figure 1.4 Effects of MnPN stimulation on EEG patttern and PLH neuronal activity. Upper An MnPN 6 s stimulus train suppressed PLH neuronal discharge, evoked EEG synchronization, and reduced EMG activity. The sweep display shows effects of successive stimulus trains. The events display shows averaged PLH neuronal discharge rate in conjunction with train stimulation. Lower Raster plot showing neuronal discharge during single pulse stimulation. In this example, PLH neuronal activity was inhibited with a latency of about 10 ms inhibition lasted about 110 ms. Activation of MnPN neurons during NREM sleep would result in suppression of PLH neuronal activity.

Some evidence supports a hypothesis that the POA hypnogenic system also plays a role in homeostatic control of sleep. Homeostatic control of NREM sleep refers to compensatory increases in sleep amounts and particularly in EEG slow wave activity (SWA, usually 0.5-4 Hz) after sleep deprivation. SWA is the hallmark of homeostatic control. SWA gradually declines within sustained sleep, as homeostatic drive for sleep is satisfied. A role for the POA in homeostasis is suggested by the following observations. 

IL-ip is a well documented sleep factor (reviewed by Obal Krueger, 2003). Its administration increases sleep, its blockade decreases sleep and sleep rebound, and its transcription increases during waking. IL-1 receptor knock-out mice sleep less. Local application of IL-1 p in POA also stimulates NREM sleep. We examined the effects of local administration of IL-1 p and an antagonist through microdialytic application adjacent to lateral POA neurons (Alam et at, 2004). Neuronal activity is recorded within 0.5-1.0 mm of a microdialysis membrane in unrestrained rats. IL-ip potently inhibited the activity of 79% of wake-active neurons. The inhibitory response to IL-ip of wake-active neurons could be blocked by pre-treatment with IL-lra, an IL-ip antagonist. IL-ip application also excited some sleep-active neurons, but this response was inconsistent. 

McGinty, D. Szymusiak, R. (2001). Brain structures and mechanisms involved in the generation of NREM sleep focus on the preoptic hypothalamus. Sleep Med. 

Sagales, T., Erill, S. Domino, E. F. (1969). Differential effects of scopolamine and chlorpromazine on REM and NREM sleep in normal male subjects. Clin. Pharmacol. Then 10, 522-9. 

The hypothesis of the role of HA in wakefulness stems from the observation that administration of the classical antihistamines (i.e. H3 receptor antagonists) induced sedation. These first-generation antihistamines, used to treat inflammatory reactions, could cross the blood-brain barrier and block the central Hi receptor (White Rumbold, 1988). The first study examining the effect of antihistamines on sleep-wakefulness in cats reported an increase in NREM sleep and a decrease in REM sleep (Jewett, 1968). Similar results were also obtained in dogs (Wauquier et ah, 1981) and humans (Risberg et ah, 1975 Bassano Caille, 1979 Nicholson et ah, 1985 Adam Oswald, 1986). Intraventricular application of HA in the anesthetized rat caused a dose-dependent decrease in the duration of narcosis, whereas intraventricular application of HA in conscious... 

Infusion of prostaglandin D2 (200 pmol/min) or the adenosine A2a receptor agonist CGS21680 (20 pmol/min) for 2 h into the subarachnoid space under the BF, during the dark period, increased NREM sleep and reduced c-Fos protein in the TMN of rats when compared with saline-treated controls (Scammell et al., 1998, 2001). In contrast, infusion of the adenosine Ai receptor agonist N6-cyclopentyl-adenosine (2 pmol/min) in the same area did not have any effect on sleep-wakefulness or c-fos expression in the TMN. 

A significant decrease in wakefulness with a concomitant increase in NREM sleep was also seen with systemic (20 mg/kg) or local application of a-FMH (50 pg in 1 pi) in the TMN region of cats. Although the sleep-inducing effect of a-FMH began 8 h after systemic administration and lasted for one day (Lin et at, 1988), the sleep-inducing effect appeared within 2 h of local application and its most prominent effect lasted for 9 h. In contrast, local microinjections of SKF-91488 (50 pg in 1 pi), a specific inhibitor of the catabolic enzyme HMT, produced an immediate increase in wakefulness, with a concomitant decrease in NREM and REM sleep that lasted for 6 h (Lin et at, 1986). 

Administration of HA and its effect on sleep-wakefulness Local application of HA (5, 30 and 60 pg) in the TMN region of cats increased the latency to sleep, increased arousal, and reduced NREM sleep in a site-specific, dose-dependent manner. The highest dose produced the maximal effect, which lasted for 6 h. The HA-induced arousal was completely blocked when the cats were pretreated intraperitoneally with the Hi receptor antagonist mepyramine (Lin et at, 1986, 1988). In rats, intraventricular administration of HA blocked the increase in delta and theta activity (0-6 Hz) in the EEG induced by repeated low-frequency stimulation of the midbrain reticular formation. This effect was blocked if specific thalamic nuclei were lesioned (Tasaka et at, 1993) or by simultaneous administration of an Hi receptor antagonist, but not by an H2 receptor antagonist (Tasaka et at, 1989). Application of HA... 

Systemic administration of the Hi receptor antagonists pyrilamine and diphenhydramine decreased wakefulness and increased NREM sleep in rats (Monti et al., 1986) conversely, intracerebroventricular application of the... 

Hi-receptor agonist 2-thiazolylethylamine dose-dependently increased wakefulness and decreased both NREM sleep and REM sleep. Furthermore, the Hi receptor antagonist pyrilamine blocked the wakefulness-inducing effects of the Hi-receptor agonist 2-thiazolylethylamine (Monti et al., 1986). 

Similar results were obtained in cats. Intraperitoneal injections of the Hi receptor antagonist mepyramine (1 and 5 mg/kg) dose-dependently increased NREM sleep and decreased wakefulness, REM sleep, and the latency to sleep within 1 h of injection (Lin et al., 1988). Similarly, local application of mepyramine (120 pg in 1 pi) into the TMN region increased NREM sleep, with a concomitant decrease in wakefulness within 1 h of injection. However, unlike the systemic injection, the latency to sleep remained unchanged and REM sleep was significantly increased following local injection of mepyramine in the TMN region (Lin et al., 1988). 

Local administration of the Hi agonist 2-thiazolylethylamine (50 pg in 0.5 pi) into the pontine tegmentum increased wakefulness and reduced NREM sleep during the first 3 h after injection. In contrast, local application of mepyramine (5 pg in 0.25 pi) caused a decrease in wakefulness and an increase in NREM sleep. 

Although systemic administration of thioperamide in rats induced a dose-dependent increase in wakefulness with a concomitant reduction in NREM and REM sleep, systemic administration of (R)a-methylhistamine had no effect (Monti et al., 1991). In contrast, bilateral application of (R)a-methylhistamine into the TMN region of rats increased NREM sleep with a concomitant decrease in wakefulness and REM sleep. The NREM-sleep-inducing effect of (R)a-methylhistamine was attenuated if the rats were pretreated with thioperamide (4.0 mg/kg) (Monti et al, 1991). 

Oral administration of the H3 receptor agonist BP 2.94 (20-30 mg/kg) to rats produced a dose-dependent increase in NREM sleep without a significant change in wakefulness or REM sleep. With the highest dose of BP 2.94 (30 mg/kg), the increase in NREM sleep was observed during the second hour and the effect lasted for 6 h. Pretreatment with the H3 receptor antagonist carboperamide (30 mg/kg) prevented the sleep-inducing effects of BP 2.94. In contrast, oral administration of carboperamide (20-30 mg/kg) produced a dose-dependent increase in wakefulness with a concomitant decrease in NREM and REM sleep (Monti et al., 1996). 

In order to explore the importance of the H3 receptor in sleep-wakefulness, Toyota et al. (2002) compared the wake-promoting effects of the H3 receptor antagonist thioperamide in wild-type and H3 receptor KO mice. In wild-type mice, subcutaneous administration of thioperamide (10 mg/kg) increased wakefulness with a concomitant decrease in NREM sleep during the first 2 h after administration at lights-on. REM sleep was unaffected. In contrast, thioperamide had no effect on sleep-wakefulness in H3 receptor KO mice (Toyota et al., 2002). 

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