SLEEP

Kimura, Toshiyuki; Ho, Ing Kang; Yamamoto, Ikuo

doi: 10.1093/sleep/24.3.251pmid: 11322706

Abstract:This review deals with the concept of sleep mechanism based on our uridine receptor theory. It is well established that uridine is one of the sleep-promoting substances, we have, therefore, synthesized new types of hypnotic compounds from oxopyrimidine nucleosides. Their mechanism of action in CNS depressant effects is elucidated based on the receptor theory. In this study, structure-activity relationship for CNS depressant properties, sleep-promoting effects, interaction with certain CNS receptors, and receptor binding assay of uridine derivatives as oxopyrimidine nucleoside were investigated.In the studies of structure-activity relationship of N3-substituted uridine, we found for the first time that both N3-benzyluridine and N3-phenacyluridine synthesized exhibited potent hypnotic activity (loss of righting reflex) by intracerebroventicular injection in mice. Moreover, certain derivatives of these compounds possessed synergistic effects with barbiturate and benzodiazepine, and decreased in spontaneous activity, motor incoordination, and antianxiety effects in mice. Especially, N3-phenacyluridine markedly enhanced pentobarbital- and diazepam-induced sleep by 6- and 70-fold, respectively. However, N3-benzyluracil and N3-phenacyluracil that have no ribose moiety did not possess any hypnotic activity, indicating specific effects of nucleoside derivatives. Effects of N3-benzyluridine on natural sleep in rats were thus examined. N3-Benzyluridine also possessed the sleep promoting effect assessed by electrocorticogram at the dose of 10 pmol. For elucidating the mechanism of action of N3-phenacyluridine, the interactions of this compound with benzodiazepine, GABA, 5-HT, or adeno-sine receptors were also investigated. Although the pharmacological activity of N3-phenacyluridine was high, the affinities to benzodi-azepine, GABA, 5-HT, and adenosine receptors were quite low. [3H]N3-Phenacyluridine concentration-dependently bound to synaptic membrane prepared from the bovine brain. The Scatchard analysis revealed a single component of the binding site. This binding site is proposed here as a novel receptor called “uridine receptor” for hypnotic activity of the uridine derivatives. The rank order of the distribution of these specific binding sites was found to be striatum > thalamus > cerebral cortex > cerebellum > mid brain > medulla oblongata in the rat brain. In the metabolic study of N3-phenacyluridine, we found that this compound was exclusively metabolized to N3-(S)-(+)-α-hydroxy-β-phenethyluridine, but not the (R)- form, in mice. N3-(S)-(+)-α-Hydroxy-β-phenylethyluridine possessed not only strong hypnotic activity but also a high affinity to the uridine receptor of synaptic membranes, while the (R)-isomer was low in both activities. Racemic mixture was shown to be intermediate for pharmacological effects of the compounds. These studies which used (R)- or (S)-isomer indicate that uridine binding site or uridine receptor, exists in the CNS and plays some role in sleep regulation in mammals as one of the triggering steps in inducing hypnotic activity.It is suggested that uridine is released from steps of nucleic acid-nucleic protein biosynthesis (catabolism), and reaches the binding sites in the areas of the brain which regulate natural sleep. The uridine dissociated from the receptor is then utilized for the synthesis of nucleic acid (anabolism). We propose here that the induction of sleep may be mediated by uridine through uridine receptor in the CNS, although the structure of uridine receptor is not yet elucidated.

Churchill, Lynn; Taishi, Ping; Guan, Zhiwei; Chen, LiChao; Fang, Jidong; Krueger, James M.

doi: 10.1093/sleep/24.3.261pmid: 11322707

AbstractStudy objectives:Determine the effects of time of day and sleep deprivation on glutamate decarboxylase 67,000 MW (GAD67) mRNA during cortical synaptic reorganization induced by a unilateral trimming of the mystacial vibrissae in rats.Design:Two experiments were conducted—One measured GAD67 mRNA in the barrel cortex at 3 or 6 h after a unilateral whisker cut at either light or dark onset; the other measured GAD67 mRNA after a unilateral whisker cut at light onset with or without sleep deprivation.Setting:University-based Research LaboratoryParticipants:Sprague-Dawley rats (250–350 g)Interventions:N/AMeasurements and Results:The reverse transcriptase polymerase chain reaction was used to measure the time of day changes in GAD67 mRNA after a unilateral whisker cut. GAD67 mRNA decreased in the barrel cortex at 3 and 6 h after a whisker trim at dark onset when the rats were mainly awake. No changes were observed in GAD67 mRNA levels after a whisker cut at light onset, a time when the rats mainly sleep. In situ hybridization for GAD67 mRNA supported these findings; no changes in GAD mRNA occurred in layer 4 of the barrel cortex that received input from the mystacial whiskers that were trimmed at light onset. However, when the rats were sleep-deprived, GAD67 mRNA increased in the barrel cortex receiving input from the lip hairs surrounding the trimmed mystacial whiskers.Conclusions:These data imply that sleep modifies GAD67 mRNA expression and that this effect is dependent upon the nature of the ongoing synaptic reorganization. They support the notion that sleep serves a synaptic function.

Alfred J., Lewy

doi: 10.1093/sleep/24.3.271pmid: N/A

Yang, Chien-Ming; Spielman, Arthur J.; D'Ambrosio, Paul; Serizaw, Shiro; Nunes, Joao; Birnbaum, Jason

doi: 10.1093/sleep/24.3.272pmid: 11322709

AbstractStudy Objectives:This study was designed to test the hypotheses that a delayed weekend sleep pattern may lead to a phase delay of the endogenous circadian rhythm, and that melatonin administration can counteract the phase delay and prevent the sleep and functional impairments associated with this sleep pattern.Design:A within-subject, counterbalanced design was used in which each subject participated in both placebo and melatonin conditions. Subjects’ sleep-wake schedules were delayed by two hours on Friday and Saturday to simulate the delayed weekend sleep pattern. Six mg of mela-tonin or a placebo pill was administered double blind on Sunday late afternoon.Setting:N/AParticipants:Ten healthy volunteers (mean age = 22.1 years old).Measurements and Results:Salivary dim-light melatonin onset (DLMO) was measured on Friday and Monday nights. Subject's sleep was recorded with polysomnography on Sunday night and their levels of sleepiness, cognitive functioning and mood were assessed on Sunday night and Monday morning. Results show that the delayed weekend sleep pattern caused a 31.6 min delay of the endogenous melatonin rhythm. Melatonin administration counteracted the phase delay of endogenous melatonin onset. On Sunday, melatonin administration increased the sleepiness throughout the evening and reduced sleep onset latency at bedtime. On Monday morning, subjective sleepiness was decreased in the melatonin condition.Conclusion:A delayed weekend sleep pattern did show a mild phase-delay effect on the endogenous circadian rhythm. A single dose of mela-tonin can acutely reverse the weekend drift.

Larrosa, Oscar; de la Llave, Yolanda; Barrio, Soledad; Granizo, Juan Jose; Garcia-Borreguero, Diego

doi: 10.1093/sleep/24.3.282pmid: 11322710

AbstractStudy objectives:To investigate potential stimulant and anticataplectic effects of 10 mg reboxetine in patients diagnosed with narcolepsy.Design:12 patients were treated for a 2-week period with 10 mg reboxetine under open conditions. The dosage of reboxetine was gradually increased between Day 1 and Day 9. Outcome parameters consisted of nightime polysomnography (PSG), Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (ESS), Visual Analog Scale for Sleepiness (VAS), Ullanlinna Narcolepsy Scale (UNS), and the Beck Depression Inventory (BDI).Setting:Sleep Disorders Clinic at a University Hospital.Patients:12 patients meeting ICSD-criteria for narcolepsy.Interventions:Pharmacological treatment with reboxetine.Results:Following treatment for two-weeks, a significant improvement in daytime sleepiness could be observed, as reflected by a mean decrease of 48.6% on the Epworth Sleepiness Scale and a mean increase of 54.7% in sleep latency on the MSLT. Furthermore, a significant reduction in the cataplexy subscore of the Ullanlinna Narcolepsy Scale and in REM-sleep was found.Conclusions:Our results suggest that reboxetine exerts stimulant and anticataplectic effects in narcolepsy. Contrary to previous thinking, by which stimulant action would require dopaminergic facilitation, noradrenergic mechanisms might be relevant to the control of wakefulness.

Berg, Soren

doi: 10.1093/sleep/24.3.289pmid: 11322711

Abstract:The effect of reducing reverberation time was studied in 12 subjects during sleep. EEG-arousals following specific sound stimuli were significantly reduced (p<0.007) when reverberation time was reduced with sound-absorbing ceiling-tiles. On average reverberation was reduced 0.124 seconds at similar sound levels.It is proposed that increased sound absorption, i.e. reduced reverberation time, by contributing to a better acoustic environment may reduce sound-induced sleep fragmentation.

Tietzel, Amber J.; Lack, Leon C.

doi: 10.1093/sleep/24.3.293pmid: 11322712

AbstractStudy Objectives:The purpose was to remedy the lack of experimental studies directly comparing the effects of brief and long daytime naps following nocturnal sleep restriction.Design:Twelve young adult healthy sleepers participated in a repeated measures design comparing the effects of no nap, a 10-minute nap, and a 30-minute afternoon nap in each case following a night of 4.7 hours of total sleep time. Objective and subjective alertness measures and cognitive performance measures were taken before, then 5, 35, and 60 minutes after the termination of the nap.Setting:N/AParticipants:N/AInterventions:N/AMeasurements and Results:In the no nap condition measures showed either no change or a decreases of alertness and performance across the testing period. Following the 10-minute nap there was an immediate improvement in subjective alertness and cognitive performance which was sustained for the hour of post nap testing. Immediately following the 30 minute nap most measures of alertness and performance declined but showed some recovery by the end of testing.Conclusions:Because the delayed benefits following the 30-minute nap may be due to sleep inertia, longer post-nap testing periods should be investigated. However, we conclude that the detrimental effects of sleep restriction were more rapidly and significantly ameliorated, at least within the hour following the nap, by a 10-minute afternoon nap.

Corkum, Penny; Tannock, Rosemary; Moldofsky, Harvey; Hogg-Johnson, Sheilah; Humphries, Tom

doi: 10.1093/sleep/24.3.303pmid: 11322713

AbstractStudy Objectives:To assess various sleep parameters in latency-aged children with ADHD and their normally developing peers through the use of multiple sleep measures.Design:Six sleep parameters were evaluated for two groups of children, ADHD and normal comparison. Each group consisted of 25 children (20 males, 5 females) who ranged in age from 7 to 11 years. All children underwent rigorous diagnostic procedures and the ADHD subjects were selected only if they displayed pervasiveness in their symptomatology and were medication naive. Parents completed a retrospective questionnaire which evaluated sleep problems over the past six months. Additionally, each child wore an actigraph for seven consecutive nights, and the child's parents completed a sleep diary during this time period.Setting:N/APatients or Participants:N/AInterventions:N/AResults:Based on the findings from the questionnaire, parents of children with ADHD reported significantly more sleep problems than parents of normally developing children. However, the majority of these sleep differences were not verified through actigraphy or sleep diary data, with the exception of longer sleep duration for children with ADHD and parent reports that describe increased bedtime resistence. It was also found that child-parent interactions during bedtime routines were more challenging in the ADHD group.Conclusions:Despite the possibility of intrinsic sleep problems such as longer sleep duration, results indicate that many of the sleep problems of children with ADHD may be due to challenging behaviours during bedtime routines. The reason for discrepancies among sleep studies employing objective measures as well as between retrospective and prospective measures are discussed.

Chervin, Ronald D.; Archbold, Kristen Hedger

doi: 10.1093/sleep/24.3.313pmid: 11322714

AbstractStudy Objectives:Children with sleep-disordered breathing (SDB) or periodic leg movements during sleep (PLMS) often have hyperactive behavior that improves when the sleep disorder is treated. Some children with SDB also have PLMS. To determine what polysomnographic features of SDB might be associated with hyperactive behavior, we studied behavior, SDB, and PLMS in a series of patients.Design:Prospective and observationalSetting:University-based sleep disorders laboratorySubjects:Children (n=113) aged 2 to 18 years, referred for suspected SDBInterventions:Parents completed the hyperactivity index of the Connors’ Parental Rating Scale, and results were converted to age-adjusted t-scores. Children underwent laboratory-based polysomnography, with esophageal pressure monitoring when requested (n=19) by referring physicians.Results:Children with SDB (n=59) showed high hyperactivity scores (mean 59.5±18.3 SD, 95% C.I. [54.7, 64.2]) but these scores were no higher than those of children without SDB (59.0±15.1, [54.8, 63.1]). Hyperactivity showed no significant associations with the rate of apneas and hypopneas, minimum oxygen saturation, or most negative esophageal pressure (p<0.10), but was associated with the presence of 5 or more PLMS per hour (p=0.02). The rate of PLMS showed a linear association with hyperactivity among those subjects with SDB (p = 0.002), but no association among those subjects without SDB (p = 0.64).Conclusions:These findings suggest that hyperactive behavior is common among children referred for suspected SDB, regardless of the presence or severity of SDB. Current observations cannot prove causality, but they are consistent with the hypothesis that PLMS may contribute to hyperactivity and SDB may act as an effect modifier.

Han, Fang; Chen, Erzhang; Wei, Hailing; Dong, Xiaosong; He, Quanying; Ding, Dongjie; Strohl, Kingman P.

doi: 10.1093/sleep/24.3.321pmid: 11322715

AbstractStudy Objectives:The purpose is to report the results of an effort to diagnose children with narcolepsy in a pediatric referral clinic.Design:Between September 1998 and December 1999, a program was implemented to emphasize recognition of childhood narcolepsy. Patients underwent brain computed tomography (CT) scan and magnetic resonance imaging (MRI) testing. All children received a MSLT test following a routine night's sleep, and serological HLA typing for HLA DR2. Three who reported occasional snoring also underwent nocturnal PSG prior to the MSLT.Setting:N/APatients or Participants:N/AInterventions:N/AMeasurements and Results:29 (21 male, 8 female) children were identified with sleepiness and cataplexy. There was no evidence for brain functional or structural disease or for drug use. Sleep paralysis was elicited in 41%; hypnagogic hallucinations, in 59%. Psychosocial problems including emotional irritability and social isolation were present in 93% of the patients. Mean sleep latency on MSLT was 2.0±1.3 minutes; sleep-onset rapid eye movement (SOREM) occurred during 2/5 naps in 28 of 29 patients and 3/5 in 26/29 patients. The average number and latency of SOREM episodes were 4.2±0.9 episodes and 4.0±1.7 minutes, respectively. In those with snoring, a nocturnal PSG did not disclose sleep apneas/hypopneas. All patients but one were HLA DR2 positive. The estimated clinic incidence was 0.04%.Conclusions:A program for recognition in a referral neurology clinic combined with an availability of the MSLT and HLA testing resulted in the new identification in North China of a number of children with narcolepsy syndromes.