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A novel objective technique, the emotion spectrum analysis method, was first applied to investigate emotional fluctuations before, during and after a daytime nap in eight healthy young adults (four males and four females). The subjects were allowed to freely nap between 13.00 and 14.00 h, in which stages 1 and 2 non-rapid eye movement sleep occurred on average for 5.9 and 20.8 min, respectively. Emotional components such as anger, joy, relaxation and sadness were numerically estimated on the basis of spatio-temporal behavior of 21-channel electroencephalogram and analyzed statistically. In comparison with the prenap waking level, the magnitudes of the anger, joy and relaxation components remained stably unchanged during the nap but elevated significantly during the postnap waking period. The sadness component exhibited little significant change throughout the observation period. From the results, we suggest that a short daytime nap modulates the emotions to improve the postnap mental states.

We studied the effect of sleep excess on the sleep-wakefulness pattern of rats. Subarachnoid infusion of prostaglandin D2 or the adenosine A2a receptor agonist CGS21680 effectively induced slow wave sleep (SWS) for the first 12 h of the night-time period, whereas they did not induce sleep during the following 24 h of infusion. An increase in the amount of wakefulness was seen during the last 12 h of prostaglandin D2 infusion. The amounts of wakefulness strongly increased during the following 36-h recovery period. Rebound wakefulness was extraordinarily strong after the cessation of CGS21680 infusion, reaching almost complete insomnia during the night-time. Treatment of animals with prostaglandin D2 overnight, following by treatment with CGS21680 on the next night, resulted in the strongest induction of wakefulness rebound. During the rebound period, the amount of wakefulness reached up to 50 min per hour in the daytime. Rebound of wakefulness depended on the amounts of preceding SWS induced by infusion of prostaglandin D2 for 6 or 12 h and of CGS21680 for 12 h. The larger the amount of SWS, the larger the amount of the following rebound of wakefulness. Rebounds of wakefulness occurred as a result of decrease in SWS amounts, whereas paradoxical sleep amounts did not change. Desensitization of adenosine A2a receptors and accumulation of prostaglandin E2 may be involved in the production of strong wakefulness rebound following relatively long treatments (more than 12 h) with prostaglandin D2 or CGS21680.

In order to investigate the circadian oscillatory system, the present study performed simultaneous and continuous recordings of brain and intraperitoneal temperatures, drinking and locomotion in rats under light-dark (LD) cycles and continuous dim illumination (dim LL) for a total period of 16 days. Compared to circadian amplitudes under LD, those under dim LL were significantly reduced by 34% for drinking and 50% for locomotion, but were not for brain and intraperitoneal temperatures. On the other hand, means of steady circadian periods during last 10 days under dim LL were all within a close range between 24.2 and 24.3 h in these rhythms. Besides the steady periods, one rat exhibited weak circadian period of 23.7 and 24.6 h, but these multiple frequencies were also equally observed in the four rhythms. The similarity in the periodicities suggests that these temperature and activity rhythms might be driven by a common oscillatory system. Therefore differential reductions in the amplitudes of drinking and...

The whole brain content of vitamin B12 (VB12) in the rat was assayed by the chemiluminescent immunoassay at 4 h intervals in 12:12 h light-dark cycles (LD) and five different circadian times (CTs) under constant dim illumination (dim LL). In LD-entrained rats, the content of VB12 exhibited a day-night rhythm with a peak 2 h after the dark onset time and a trough 2 h before the light onset time. In freerunning rats under dim LL, the content of VB12 also exhibited a circadian variation with a peak ca. 2 h after the activity onset time (CT14) and a trough ca. 12 h after the activity onset time (CT 0). These findings clearly indicate that the brain VB12 content decreased during the active phase and increased during the resting phase regardless of the lighting schedule. On the other hand, the drinking behavior, as an index of the intake activity, was observed less frequently in the light phase of LD cycles and the resting phase of dim LL. Since most of the digested VB12 is known to be continuously stored in the liver, it is demonstrated that the rhythm of the brain content of VB12 may be caused by brain consumption of VB12 during the active phase and the transportation from the peripheral storage during the resting phase, independent of intake activities.

The purpose of this study was to evaluate changes in sleep patterns during pregnancy to better understand sleep regulation during pregnancy. We uninterruptedly recorded electroencephalogram (EEG), electromyogram (EMG), and brain temperature (Tbr) throughout pregnancy in rats. The duration of non-rapid eye movement (non-REM) sleep decreased after day 5 of pregnancy associated with an inverse increase in the number of non-REM sleep episodes. Thus, the amount of total non-REM sleep time remained constant throughout pregnancy. The amount of total REM sleep time decreased on day 17 of pregnancy after which the reduced state was sustained. That was mainly due to a decrease in the number of REM sleep episodes. Brain temperature (Tbr) gradually decreased as pregnancy advanced, reaching its lowest value 3 days before delivery. These observations provide a better understanding of the sleep patterns during pregnancy, and useful information for investigation of mechanisms of sleep regulation during pregnancy.

We previously reported a marked enhancement of nocturnal sleep in pregnant and pseudopregnant rats and suggested a possible involvement of prolactin (PRL) in the modulation of sleep during pregnancy. In the present study, the release of PRL was blocked by a dopamine agonist, bromocriptine (CB-154), and time-course changes in sleep were analyzed in pregnant rats. After pregnancy was induced by fertile mating with males (Day 1), rats (n = 5) were injected with 1 mg of CB-154 subcutaneously 3 h before the onset of darkness for a 3-day period (Days 1-3 or 6-8). Electroencephalogram and electromyogram for evaluating the state of sleep and wakefulness were monitored continuously up to the reappearance of an estrous cycle in the treated rats. The CB-154 treatment resulted in abortion in all rats and suppressed the pregnancy-associated nocturnal increase in non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS). The CB-154 treatment also decreased the diurnal amount of NREMS significantly. The sleep-suppressing effect of CB-154 on Days 6-8 was induced more promptly than that on Days 1-3. In the night of proestrus following the termination of pregnancy (Day 4 or Day 12), both NREMS and REMS decreased to the baseline level observed at prepregnant proestrus. Thus, our results indicated that CB-154 neutralized the pregnancy-associated sleep changes, which might be due to the inhibition of the PRL release. It is suggested that PRL is at least partially responsible for the regulation of sleep during pregnancy.

Vitamin B12 (VB12) is known as a putative modulator for the mammalian circadian clock. In an attempt to analyze the mechanism by which VB12 modulates the clock system, circadian time (CT) dependency of two VB12 analogs, methylcobalamin (methyl‐B12) and cyanocobalamin (cyano‐B12), was investigated by means of recording sleep‐wake and brain temperature (Tbr) rhythms over 3 weeks in rats freerunning under continuous dim illumination (dim LL). A 3‐h intracerebroventricular infusion of methyl‐B12 (30 nmol) was‐done at three different CT phases such as CT 12–15 (starting at activity onset), CT 18–21 (starting mid at active period) and CT 0–3 (starting at activity offset). A significant enhancement of both non‐rapid‐eye‐movement sleep and rapid‐eye‐movement sleep in phase with a significant reduction of Tbr was acutely induced during the late subjective night by the administration of methyl‐B12 at CT 12–15 and at CT 18–21. In contrast, sleep and Tbr were little affected by the infusion at CT 0–3. Subseq...

The classical 'hypnotoxin theory' was followed by extensive search for an endogenous sleep substance. Brain tissues and body fluids of sleeping and sleep-deprived animals contained active sleep-inducing factors like the sleep-promoting substance (SPS). Uridine and oxidized glutathione (GSSG), two components of SPS, seem to regulate physiological sleep differentially. Uridine may facilitate the inhibitory neurotransmission at the synaptic level of the GABAA-uridine receptor complex. In contrast, GSSG may inhibit the excitatory neurotransmission at the synaptic level of the glutamate receptor. Thus, the two SPS components promote sleep by exerting a complementary action on the two major neurotransmitter systems in the brain that have mutually reciprocal functions. Further, among multidimensional functions of sleep, uridine may contribute to recover the activity of neurons, while glutathione may counteract excitotoxic events. Hence sleep at the behavioral level is a process of neuronal restitution and detoxification at the cellular level. Such a concept can be regarded as a modern version of the Ishimori-Piéron's hypnotoxin theory proposed early in this century.

In order to clarify the relationship between sleep and reproductive activities, time-course changes in sleep were analyzed in normal female rats. The state of sleep-wakefulness was continuously monitored for 4 weeks including two-consecutive 4-day estrous cycles, a 12-day pseudopregnant period and a subsequent 4-day cycle. Sleep patterns in estrous cycle were characterized by a marked reduction in nocturnal non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS) at proestrus. A significant increase in nocturnal NREMS and REMS occurred immediately after the induction of pseudopregnancy by sterile mating, lasting for the whole pseudopregnant period for NREMS and during the early and mid period for REMS. In contrast, diurnal REMS tended to decrease towards the end of pseudopregnancy. The circadian rhythm of brain temperature exhibited no reproductive activity-dependent change. The dynamic changes in sleep may correlate alterations in neuroendocrine activities specific to estrous cycles and pseudopregnancy.

Oxidized glutathione (GSSG) is an active component of sleep-promoting substance (SPS) which was originally extracted from the brainstems of 24-h sleep-deprived rats. We analyzed somnogenic and thermoregulatory activities of five doses of GSSG in unrestrained rats. A nocturnal 10-h intracerebroventricular infusion of GSSG significantly enhanced slow wave sleep (SWS) at the dosage range from 20 to 50 nmol and paradoxical sleep (PS) at 25 nmol at the expense of wakefulness during the 12-h dark period. The dose-response relations exhibited a bell shape for both SWS and PS. The administration of 25 nmol/10 h GSSG induced the maximal increase in the total time of nocturnal sleep (35% above the baseline for SWS and 86% for PS). The enhancement of sleep was mainly due to an increase in the duration of SWS episodes and in the number of PS episodes. GSSG at 25 nmol/10 h elicited significant fluctuations in brain temperature (Tbrain), biphasic hypothermal and hyperthermal reactions during the infusion period, followed by a hyperthermal state during the subsequent light period of the recovery day and then a hypothermal state during the dark period. On the basis of recent literature on the inhibitory action of GSSG on the excitatory synaptic membrane of rat brain, we speculate that the sleep-enhancing activity of GSSG was caused by its physiological modulation on the glutamatergic neurotransmission in the brain.

This is an approach to investigate topographic changes in electroencephalographic (EEG) spectral power during pre- and post-nap wakefulness as well as stages 1 (S1) and 2 (S2) NREM sleep in 12 subjects. Delta- and theta-band power significantly increased in the frontal and central regions during S1 and S2 with an increase in inter- and intra-hemispheric correlations. Beta-band power significantly increased in the frontal, central and parietal regions during S2 with an increase in interhemispheric correlation. In contrast, alpha-band power significantly decreased in the parietal-occipital regions during S1 and S2 with a decrease in interhemispheric correlation. Thus, daytime nap modulated spatio-temporal patterns of EEG power spectral patterns in wide scalp regions.

We previously demonstrated that pregnancy-associated sleep enhancement is correlated with the daily surges of prolactin (PRL). However, in spite of a surge of PRL in the proestrous night, a reduction of nocturnal sleep occurs in phase with proestrus. Therefore, to clarify the physiological role of PRL in sleep regulation during the estrous cycle, time-course changes in sleep were analyzed in bromocriptine (CB-154)-treated and/or PRL-supplemented female rats. Sleep patterns characteristic of proestrus-to-estrus were not affected by the CB-154 treatment. In contrast, nocturnal rapid eye movement sleep (REMS) was significantly increased after the PRL supplementation. The CB-154 treatment diminished the REMS-enhancing effect of PRL. Thus, the results suggest that the endogenous PRL is not crucial for the regulation of sleep during the estrous cycle, while exogenous PRL can enhance REMS.

Although several cytokines are known to be somnogenic, no study has been conducted to examine whether colony-stimulating factors (CSF) affect sleep. Therefore, we studied the effects of granulocyte-macrophage CSF (GM-CSF) and macrophage CSF (M-CSF) on sleep in rats and their possible mechanism of action. At the dose of 10 pmol, GM-CSF or M-CSF significantly increased both non-rapid eye movement and rapid eye movement (REM) sleep or REM sleep only when infused intracerebroventricularly during the dark period. When injected locally in the hypothalamus, GM-CSF and M-CSF increased nitric oxide (NO) production. Thus, NOergic neural signals in the hypothalamus may take part in the somnogenic action of CSF.

We studied basic sleep changes in pregnant rats in order to understand how pregnancy alters sleep. In the rat, pregnancy increased nocturnal non REM sleep across the entire period but increased REM sleep only in the early period. By the end of pregnancy, diurnal sleep was decreased, showing that pregnancy in rats causes biphasic sleep changes as it does in humans. Termination of pregnancy returned the enhanced sleep to baseline as in the estrous cycle. Therefore, significant changes in the pattern of sleep occurred during pregnancy in rats, suggesting that the animal model may contribute to understanding the mechanism of sleep disorders related to human pregnancy.

Nine healthy male volunteers (mean age of 24) participated in two experimental sessions of random crossover design: a bright light (5000 lux for 5 h from 00:00 to 05:00 h) session and a dim light (10 lux for 5 h from 00:00 to 05:00 h) session. Subsequently participants entered an ultra-short sleep-wake schedule for 26 h, in which a sleep-wake cycle consisting of 10-min sleep EEG recording on a bed and 20-min resting awake on a semi-upright chair were repeated. Saliva melatonin level and core body temperature was measured throughout the experiment. Bright light significantly delayed rhythms of melatonin secretion (01:58 h), core body temperature (01:12 h) and sleep propensity (02:00 h), compared as dim light session. Significant positive correlation was found between bright light-induced phase change in core body temperature and that in sleep propensity rhythm. Light-induced melatonin suppression significantly positively correlated with the phase change in core body temperature and that in sleep propensity rhythm. Assuming that light-induced melatonin suppression represents an acute impact of light on the circadian pacemaker, our results suggest that such an impact may be directly reflected in phase changes of sleep propensity and core body temperature rhythms rather than in melatonin rhythm.

The present study examines whether or not prolactin-releasing peptide (PrRP) infused intracerebroventricularly (i.c.v.) affects sleep and the release of prolactin (PRL) and growth hormone (GH) in rats. At a dose of 0.1 nmol, PrRP promoted rapid-eye-movement (REM) sleep, whereas 1.0 nmol increased both non-REM and REM sleep and 10.0 nmol enhanced only non-REM sleep. During the i.c.v. infusion of PrRP with 0.1 nmol, levels of plasma PRL were elevated, but GH levels were significantly decreased. Since it is reported that PrRP fails to induce PRL release from the male pituitary, the stimulatory effects of PrRP on PRL release observed here seem to be indirect. However, PRL stimulated by i.c.v.-infused PrRP could take part in the REM sleep-promoting activity of PrRP.

To explore the neuronal signaling mechanisms underlying sleep regulation in the rat, the present study exam- ined continuous intra-third ventricle infusion of N-ethylmaleimide (NEM), a sulphydryl reagent that inhibits Gi=o protein- coupled receptor-mediated signaling pathways. The diurnal infusion of NEM (0.01^10 Wmol/10 h) dose-dependently inhibited both non-rapid eye movement sleep and rapid eye movement sleep. A maximal dose of NEM (10 Wmol/10 h) dramatically inhibited day-time sleep (357% for non-rapid eye movement sleep and 389% for rapid eye movement sleep) with a compensatory increase of sleep during the subsequent night-time (+33% for non-rapid eye movement sleep and +259% for rapid eye movement sleep). The day-time brain temperature was also increased by NEM, demonstrating eiects of NEM on both sleep and body temperature levels. Immunostaining of the rat hypothalamus with a monoclonal antibody against the A1 adenosine receptor (A1R) was used to explore the distribution of a sleep-related Gi=o protein- coupled receptor. Robust A1R-like immunoreactivity was found in the ventromedial preoptic nucleus and the supraoptic nucleus. Fura-2-based Ca 2a imaging analysis of acute hypothalamic slices further demonstrated that the A1R agonist N 6 - cyclopentyladenosine (CPA; 200 nM) inhibited spontaneous Ca 2a oscillations and high potassium (80 mM)-induced Ca 2a £ux in the ventromedial preoptic nucleus, while NEM (100^300 WM) and an A1R antagonist 8-cyclopentyl-dipropylxan- thine (300 nM) blocked the CPA actions and increased the high potassium-induced Ca 2a £ux. From these results we suggest that NEM-sensitive G protein-coupled receptor(s) may play an important role in the regulation of sleep and body temperature in the rat and one possible mechanism is an A1R-mediated regulation of intracellular Ca 2a concentrations in the ventromedial preoptic nucleus. fl 2001 IBRO. Published by Elsevier Science 2a imaging, fura-2, GTP-binding protein, immunostaining, intracerebroventricular infusion, voltage-sensitive Ca 2a channels.

The aim of the present study was to determine the pattern of sleep disturbances and the effects on sleep of aniracetam, a cognitive enhancer, in stroke-prone spontaneously hypertensive rats (SHRSP). Compared with normotensive control rats, SHRSP exhibited an impaired sleep pattern characterized by suppressed diurnal rapid eye movement (REM) sleep and excessive nocturnal non-REM sleep. At a dose of 30 mg/kg per day p.o., aniracetam increased REM sleep in the light period after administration for 5 consecutive days. Consequently, suppressed REM sleep in SHRSP was restored by repeated treatment with aniracetam. Aniracetam could be useful in improving REM sleep impairment associated with vascular dementia.

The present study examined in rats how prolactin-releasing peptide (PrRP), a new hypothalamic hormone, infused centrally during the dark period affects sleep and plasma levels of prolactin (PRL). At a dose of 0.1 nmol, PrRP increased only rapid eye movement (REM) sleep, whereas with 1.0 nmol both non-REM sleep and REM sleep were enhanced. However, 10.0 nmol of PrRP increased only non-REM sleep with a febrile response. The levels of plasma PRL were elevated during the infusion of PrRP with 0.1 and 1.0 nmol. Consequently, the increased release of PRL correlated with significant increases in REM sleep, but not in non-REM sleep.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that may affect various functions of the CNS because the molecule and its receptors are expressed in the brain. The present study examines the effects of GM-CSF on sleep using rats and the secretion of three neurotransmitters/hormones that are involved in sleep regulation. When infused intracerebroventricularly at doses as low as 10 pmol for 10 hr during the dark period, GM-CSF promoted predominantly rapid eye movement (REM) sleep and moderate amounts of non-REM sleep without eliciting fever. An injection of GM-CSF (3.0 pmol) into the arcuate nucleus increased the release of nitric oxide (NO) from the hypothalamus but did not alter plasma levels of growth hormone. The release of somatostatin (SRIF) from the medial basal hypothalamus was stimulated by 1 × 10−11M GM-CSF. These findings indicated that centrally administered GM-CSF stimulates SRIF release through activation of the NO system in the hypothalamus. Because SRIF promotes REM sleep, it may also mediate the effects of GM-CSF on REM sleep. The present study indicates a novel central effect of GM-CSF that modulates sleep, supporting the notion that hematopoietic cytokines also play roles in the CNS.

Dissociable circadian rhythms of sleep and body temperature in primates are thought to be regulated by independent oscillators whereas the uncoupling of circadian rhythms has not been well described in other mammals. Therefore, we made simultaneous recordings of non-rapid-eye-movement-sleep (NREMS), rapid-eye-movement-sleep (REMS), brain temperature, intraperitoneal temperature, locomotion and drinking activity under light-dark (LD) and continuous dim illumination (dim LL) and analyzed their interrelations. The rhythmic patterns of body temperature, locomotion and drinking were modified on the 12th circadian day of dim LL, while the mean body temperature as well as mean occurrence of drinking and locomotor activities did not change significantly. In contrast, dim LL exposure significantly increased the total time spent in NREMS during the resting phase of dim LL and increased REMS episodes during the active phase of dim LL. The diverse effects of dim LL exposure on the recorded phenomena suggest that temporal patterns of sleep were the most sensitive to perturbations of lighting and that differential oscillatory mechanisms may regulate sleep and other circadian rhythms in the rat.

The amount of wakefulness and slow wave sleep (SWS) during the 12-h light period slightly but significantly decreased and increased, respectively, in freely behaving rats after continued 1-week intake of Panax ginseng extract through drinking water (15 mg/day). Paradoxical sleep was little affected. No sleep parameters were modulated by the treatment during the dark period. The diurnal SWS enhancement disappeared and recovered to the baseline level after 2 weeks of continued treatment. It is speculated that the well known health-improving effect of the ginseng may be, at least in part, related to an enhancement of sleep.

We previously reported regarding the "sleep-promoting substance (SPS)," which was isolated from the brainstem extract of sleep-deprived rats, the existence of multiple active components including uridine and SPS-B. Intracerebroventricular infusion of crude SPS-B exhibited significant enhancing effects on both slow wave sleep and paradoxical sleep in unrestrained rats. Further investigation of SPS-B has resulted in its final identification as oxidized glutathione (GSSG, gamma-glutamylcysteinylglycine disulfide). Authentic GSSG similarly administered in rats also significantly enhanced sleep which was indistinguishable from normal physiological sleep. We propose GSSG as a candidate endogenous sleep substance.

Effects of methylcobalamin (methyl-B12), a putative drug for treating human circadian rhythm disorders, on the melatonin-induced circadian phase shifts were examined in the rat. An intraperitoneal injection of 1-100 microg/kg melatonin 2-h before the activity onset time (CT 10) induced phase advances of free-running activity rhythms in a dose-dependent manner (ED50=1.3 microg/kg). Injection of methyl-B12 (500 microg/kg) prior to melatonin (1 microg/kg) injection induced larger phase advances than saline preinjected controls, while the injection of methyl-B12 in combination with saline did not induce a phase advance. These results indicate amplification of melatonin-induced phase advances by methyl-B12. Pinealectomy abolished the phase alternating effect of methyl-B12, suggesting a site of action within the pineal gland. In fact, methyl-B12 significantly increased the content of melatonin in the pineal collected 2-h after activity onset (CT 14). In contrast, no difference in melatonin content was found at CT 10, indicating that the effect of methyl-B12 may be gated after the activity onset time when endogenous melatonin synthesis is known to increase. These results suggest that methyl-B12 amplifies melatonin-induced phase advances via an increase in melatonin synthesis during the early subjective night at a point downstream from the clock regulation.

Experimental evidence in canine narcolepsy suggests that central cholinergic systems are critically involved in the regulation of cataplexy, an abnormal manifestation of REM sleep atonia. In the current study, we found that intracerebroventricular perfusion of methyl-B12, (10(-5)-10(-2) M), significantly aggravated cataplexy and enhanced REM sleep in narcoleptic dogs. Choline, a direct precursor of acetylcholine, was also found to aggravate cataplexy, while cyano-B12, a vitamin B12 analog without methyl donating abilities, had no effect on cataplexy. Since both methyl-B12 and choline are reported to enhance acetylcholine synthesis, enhancement of the biosynthesis of acetylcholine may be involved in the effects observed in canine narcolepsy. Our results suggest that central administration of methyl-B12 has the potential to modulate both normal and pathological REM sleep.

Sleep disorder during the course of pregnancy has been recently recognized in humans. However, the underlying mechanism of pregnancy-associated sleep disorder remains undetermined, and sleep changes even during normal pregnancy have not been fully understood. To describe the effects of pregnancy on sleep, sleep-wake patterns before and after fertile mating were compared in an animal model. Baseline recordings of sleep and brain temperature were made throughout a normal 4-day estrous cycle in female rats. After the rats became pregnant, the recordings continued across the entire pregnant period. Compared with baseline sleep before mating, both non-rapid eye movement sleep and rapid eye movement sleep increased significantly from the first night of pregnancy. Although rapid eye movement sleep returned to the baseline level from midpregnancy, nocturnal non-rapid eye movement sleep stayed enhanced during the entire pregnant period. Daytime sleep fluctuated toward the end of pregnancy. Brain temperature was elevated during the early period of pregnancy but did not correlate with enhanced sleep. The results suggest that physiological changes in different stages of pregnancy may contribute to the regulation of maternal sleep and temperature.

Microdialysis technique was applied to the medial preoptic area (mPOA) of the hypothalamus, a crucial site for the regulation of sleep, in order to analyze the interrelationship between the extracellular level of glutamate (Glu) and the vigilance states. Dialysates from the mPOA were sampled at 5-min intervals for 2-h diurnal period with a perfusion rate of 2.0 microliters/min in freely moving rats, whose sleep-waking behaviors were polysomnographically monitored. Extracellular Glu increased during wakefulness, exhibiting a peak at the transition period from wakefulness to non-rapid-eye-movement sleep (NREMS) (18.0% above the average), whereas it decreased during NREMS (9.2% below the average). It is likely that Glu in the mPOA is dynamically involved in the alterations of the vigilance states.

During the perimenopausal period, women often develop insomnia. To determine whether hormone replacement therapy (HRT) could affect sleep in menopause, the present study examined estrogen (E2) treatment in old female rats with an immune challenge. The rats received either E2 or vehicle s.c. for a week, and 5 or 50 µg/kg of lipopolysaccharide (LPS) i.p. on day 3. The old female rats showed an impaired sleep pattern, but it tended to be improved when E2 was administered. Furthermore, some non-treated rats did not respond to an LPS injection, but under E2 treatment, LPS induced significant increases in non-rapid eye movement (REM) sleep with hypothermia. The results indicate that the E2 supplement enhanced immune responses in old female rats, suggesting a possible mechanism of how HRT helps postmenopausal insomnia.

The in vivo sedative property of the total aqueous extract of the aerial portion of Vervain hastata (Verbenaceae) (TAEV) was studied in male rats to establish its scientific basis in herbal medicine. The investigation was conducted using electroencephalogram (EEG) analysis, and the barbituric-hypnosis test. The results showed that TAEV potentiated the pentobarbital-induced hypnosis significantly by reducing sleep latency and increased sleeping time in a dose-dependent manner that was reversed by flumazenil. The EEG data demonstrated that extract administration augmented total sleep time, rapid eye movement (REM) sleep and non-REM sleep at the expense of wakefulness. The study's results clearly showed the scientific validity for the use of this plant as a sedative and possibly as a nerve tonic substance.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a crucial cytokine for establishing pregnancy. It has been demonstrated previously in rats that sleep increases during early pregnancy and that centrally administered GM-CSF promotes both rapid eye movement (REM) and non-REM sleep. Therefore, whether GM-CSF is involved in pregnancy-enhanced sleep was investigated using the anti-GM-CSF antibody. Female rats received an intracerebroventricular infusion of either anti-GM-CSF or control IgG (10 microg each) for four nights from the first day of pregnancy (PD1-PD4). Although sleep amounts on PD1 were not affected, anti-GM-CSF decreased non-REM and REM sleep significantly during PD2-PD4 compared with the control baseline of the IgG group. The results demonstrated that anti-GM-CSF treatment suppresses pregnancy-enhanced sleep, suggesting that GM-CSF contributes to sleep regulation during pregnancy.

We investigated the site of action of two sleep-inducing substances, viz., muramyl dipeptide (MDP) and uridine. Localized electrolytic lesions were made bilaterally in the lateral preoptic hypothalamus (LPO) in rats and nocturnal 10-h i.c.v. infusions of MDP and uridine were performed before and after the LPO lesions. MDP increased only slow-wave sleep (SWS) in both intact and LPO-lesioned rats. Uridine promoted both SWS and paradoxical sleep (PS) before the LPO lesions whereas it increased only PS after the lesions. These results suggest that the LPO is crucial for SWS-promoting action of uridine but not MDP.

In an attempt to investigate the effects on sleep modulation of order of administration of two substances, sequential intracerebroventricular (ICV) infusions of muramyl dipeptide (MDP, 1.0 nmol) and uridine (5.0 pmol) were conducted in freely behaving rats. To eliminate the influence of intermittent infusions on their behavior, the rats were continuously ICV infused with physiological saline solution, which did not affect their normal sleep-wakipg dynamics. Under these experimental conditions, uridine infusion (2400-0500 h) attenuated the enhancement of slow-wave sleep (SWS) caused by prior infusion of MDP (1900–2400 h) to the baseline level and, thus, did not exert a sleep-promoting property. In contrast, MDP infusion (2400-0500 h) further potentiated the SWS-enhancing activity of preinfused uridine (1900–2400 h). A single infusion of MDP or uridine (2400-0500 h) similarly enhanced SWS. These results demonstrate that observed differences in the induction and maintenance of sleep are dependent upon the order of exogenously infused uridine and MDP. The time sequence per se of these sleep substances may be responsible for the differential temporal changes in sleep. It is. therefore, assumed that a crucial order of multiple sleep substances may dynamically and differentially regulate sleep in the brain.