Hypnotic activity of melatonin

OBJECTIVE: To establish the effect of melatonin upon nocturnal and evening sleep. METHODS: Experiment I: The effect of melatonin (0.1, 0.5, 1.0, 5.0, and 10 mg), ingested at 23:30, was studied on nocturnal sleep (23:30-07:30) and core body temperature in 8 healthy volunteers. Performance was measured 8.5 h post-ingestion. On completion of the experiment dim light melatonin onsets (DLMO) were determined. Experiment II: The effect of melatonin (0.5, 1.0, 5.0, and 10 mg), ingested at 18:00, was studied on evening sleep (18:00-24:00) and core body temperature in 6 healthy volunteers. Performance was measured 6.5 h post-ingestion. Each experiment was placebo-controlled and double-blind with a cross-over design with temazepam (20 mg) as an active control. RESULTS: Experiment I: Melatonin (5 mg) reduced the duration of stage 3 in the first 100 min of sleep. Melatonin (0.1 mg) reduced body temperature 6.5 to 7 h post-ingestion. Temazepam increased stage 2, reduced wakefulness and stage 1, and increased the latency to REM sleep. Temazepam reduced body temperature 4.5 to 6.5 h post-ingestion. There were no changes in performance compared with placebo. DLMO occurred between 20:40 and 23:15. Experiment II: Melatonin (all doses) increased total sleep time (TST), sleep efficiency index (SEI) and stage 2, and reduced wakefulness. Temazepam increased TST, SEI, stage 2 and slow-wave sleep, and reduced wakefulness. There were no changes in body temperature or performance compared with placebo. CONCLUSION: Melatonin given at 23:30 has no significant clinical effect on nocturnal sleep in healthy individuals. Hypnotic activity of melatonin when given in the early evening (presumably in the absence of endogenous melatonin) is similar to 20 mg temazepam.     

Day-time melatonin administration: Effects on core temperature and sleep onset latency

Significant hypothermic and hypnotic effects have been reported for melatonin at a wide range of doses. It has been suggested that this decrease in core temperature (Tc) following melatonin administration may mediate the observed increase in sleepiness. To test this, melatonin was administered to young adults during the day, and the concurrent effects on Tc and sleep onset latency (SOL) were recorded. Sixteen healthy males received either a 5 mg oral formulation of melatonin or placebo at 14.00 hours. Core temperature was recorded continuously. Sleep onset latency to stage 1 (SOL1) and stage 2 (SOL2) were recorded using an hourly multiple sleep latency test (MSLT). Compared with placebo, melatonin significantly decreased Tc 1.5 h after administration for 6 h. Between 15.00 and 18.00 hours, the drop in Tc was associated with a concurrent decrease in SOL1 and SOL2. Following administration mean SOL1 and SOL2 were reduced by 40 and 25%, respectively. In this study, daytime melatonin administration produced a significant decrease in Tc with a corresponding decrease in SOL. Taken together, these data are not inconsistent with the suggestion that melatonin may facilitate sleep onset via a hypothermic effect. In addition, this study provides support for the idea that melatonin may play a role in regulating circadian and/or age-related variations in sleep/wake propensity. From a practical perspective, exogenous melatonin may be useful in the treatment of sleep disorders associated with increased nocturnal Tc.     

Neurobehavioural performance effects of daytime melatonin and temazepam administration

Exogenous melatonin is a potential treatment for circadian disruption and insomnia. Hence, it is important to determine and quantify neurobehavioural performance effects associated with its use. The present study compared neurobehavioural performance following administration of melatonin and the benzodiazepine temazepam, using a within-subjects design. Following a training day, 16 healthy, young subjects (six males, 10 females; mean age +/- SEM, 21.4 +/- 6 years) participated in a 3-day protocol. After sleeping overnight in the laboratory, subjects completed a battery of tests at hourly intervals between 08:00 and 11:00 hours and at two hourly intervals between 13:00 and 17:00 hours. The neurobehavioural performance tasks included: unpredictable tracking, spatial memory, vigilance and logical reasoning. Subjective sleepiness was measured at hourly intervals using a visual analogue scale. At 12:00 h subjects were administered a capsule containing 5 mg melatonin, 10 mg temazepam or placebo, in a randomized, double-blind crossover fashion. A significant drug x time interaction was evident on the unpredictable tracking, spatial memory and vigilance tasks (P < 0.05). Greater changes in performance were evident following temazepam administration than melatonin administration, relative to placebo. Administration of melatonin or temazepam significantly elevated subjective sleepiness levels, relative to placebo (P 相似文献   

Effects of nocturnal bright light on saliva melatonin, core body temperature and sleep propensity rhythms in human subjects

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.     

A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome

OBJECTIVE: The effects of exogenous melatonin on sleep, daytime sleepiness, fatigue, and alertness were investigated in 22 patients with delayed sleep phase syndrome whose nocturnal sleep was restricted to the interval from 24:00 to 08:00 hours. This study was a randomized, double-blind, placebo-controlled crossover trial. Subjects received either placebo or melatonin (5 mg) daily for 4 weeks, underwent a 1-week washout period, and then were given the other treatment for an additional 4 weeks. Patients could take the melatonin between 19:00 and 21:00 hours, which allowed them to select the time they felt to be most beneficial for the phase-setting effects of the medication. METHODS: Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after 4 weeks of melatonin treatment, and after 4 weeks of placebo treatment. RESULTS: In the 20 patients who completed the study, sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time), but there was a significant decrease in total sleep time while patients were taking placebo. Melatonin did not result in altered scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from 24:00 to 08:00), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. CONCLUSIONS: Melatonin ameliorated some symptoms of delayed sleep phase syndrome, as confirmed by both objective and subjective measures. No adverse effects of melatonin were noted during the 4-week treatment period.     

Plasma melatonin rhythms in young and older humans during sleep, sleep deprivation, and wake

STUDY OBJECTIVES: To determine the effects of sleep and sleep deprivation on plasma melatonin concentrations in humans and whether these effects are age-dependent. DESIGN: At least 2 weeks of regular at-home, sleep/wake schedule followed by 3 baseline days in the laboratory and at least one constant routine (sleep deprivation). SETTING: General Clinical Research Center (GCRC), Brigham and Women's Hospital, Boston, MA. PARTICIPANTS: In Study 1, one group (<10 lux when awake) of 19 young men (18-30 y) plus a second group (<2 lux when awake) of 15 young men (20-28 y) and 10 young women (19-27 y); in Study 2, 90 young men (18-30 y), 18 older women (65-81 y), and 11 older men (64-75 y). All participants were in good health, as determined by medical and psychological screening. INTERVENTIONS: One to three constant routines with interspersed inversion of the sleep/wake cycle in those with multiple constant routines. MEASUREMENTS AND RESULTS: Examination of plasma melatonin concentrations and core body temperature. Study 1. There was a small, but significant effect of sleep deprivation of up to 50 hours on melatonin concentrations (increase of 9.81 +/- 3.73%, P <0.05, compared to normally timed melatonin). There was also an effect of circadian phase angle with the prior sleep episode, such that if melatonin onset occurred <8 hours after wake time, the amplitude was significantly lower (22.4% +/- 4.79%, P <0.001). Study 2. In comparing melatonin concentrations during sleep to the same hours during constant wakefulness, in young men, melatonin amplitude was 6.7% +/- 2.1% higher(P <0.001) during the sleep episode. In older men, melatonin amplitude was 37.0% +/- 12.5% lower (P <0.05) during the sleep episode and in older women, melatonin amplitude was non-significantly 10.9% +/- 8.38% lower (P = 0.13) during the sleep episode. CONCLUSIONS: Both sleep and sleep deprivation likely influence melatonin amplitude, and the effect of sleep on melatonin appears to be age dependent.     

Sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent

STUDY OBJECTIVES: To investigate the effects of a physiologic and a pharmacologic dose of exogenous melatonin on sleep latency and sleep efficiency in sleep episodes initiated across a full range of circadian phases. DESIGN: Double-blind placebo-controlled parallel-group design in a 27-day forced desynchrony paradigm with a 20-hour scheduled sleep-wake cycle. SETTING: Private suite of a general clinical research center, in the absence of time-of-day information. Subjects: Thirty-six healthy, 18- to 30-year-old, men (n = 21) and women (n = 15). INTERVENTIONS: Oral melatonin (0.3 mg or 5.0 mg) or identical-appearing placebo was administered 30 minutes prior to each 6.67-hour sleep episode during forced desynchrony. MEASUREMENTS AND RESULTS: Both doses of melatonin improved polysomnographically determined sleep efficiency from 77% in the placebo group to 83% for sleep episodes occurring during circadian phases when endogenous melatonin was absent. However, this remained below the average sleep efficiency of 88% observed during sleep episodes scheduled during the circadian night, when endogenous melatonin was present. Melatonin did not significantly affect sleep initiation or core body temperature. Melatonin appeared to maintain efficacy across the study and did not significantly affect percentages of slow-wave sleep or rapid eye movement sleep. CONCLUSIONS: Exogenous melatonin administration possesses circadian-phase-dependent hypnotic properties, allowing for improved consolidation of sleep that occurs out of phase with endogenous melatonin secretion during the circadian night. The results support the hypothesis that both exogenous and endogenous melatonin attenuate the wake-promoting drive from the circadian system.     

Peripheral heat loss: a predictor of the hypothermic response to melatonin administration in young and older women.

Core hypothermia following daytime melatonin administration typically displays significant interindividual variability. As this hypothermia has been associated with significant increases in skin temperature, the mechanism by which melatonin decreases core temperature may involve increasing peripheral heat loss. If so, the interindividual variability in this effect may reflect concomitant interindividual variability in heat loss capacity at the distal periphery. For six younger (mean +/- SEM: 23.4 +/- 0.3 years) and 10 older women (mean +/- SEM: 65.6 +/- 0.7 years), the maximum decrease in core body temperature following a 5-mg (p.o.) dose of melatonin was correlated with the capacity to lose heat. This was determined by the maximum increase in contralateral hand temperature following a mild positive thermal challenge (PTC). The regression analysis yielded a significant (p < 0.01) correlation of 0.80, suggesting that the individual magnitude of hypothermia following melatonin administration may reflect the capacity of an individual to dissipate heat at the distal periphery.     

Effects of humid heat exposure on human sleep stages and body temperature.

The objective of this study was to confirm the effect of humid heat exposure on sleep stages and body temperature. Seven healthy male volunteers with a mean age of 22.7+/-1.63, served as the subjects. The experiments were carried out under four different conditions of room temperature and relative humidity: 29 degrees C RH 50% (29/50), 29 degrees C RH 75% (29/75), 35 degrees C RH 50% (35/50), and 35 degrees C RH 75% (35/75). The subjects wearing only shorts slept from 23:00 to 7:00 on a bed, which was covered with a 100% cotton sheet. EEG, EOG, and mental EMG were recorded through the night. Rectal temperature (Tr) and skin temperature were measured continuously. The 35/75 condition caused more wake and a lower sleep efficiency index (SEI) and stage S3+S4 than 29/50 and 29/75. Stage REM and stage 3 were significantly decreased at 35/75 than at 29/50 and 35/50. Tr was maintained at a higher level at 35/75 than under the other conditions. Mean skin temperature was higher at 35/50 and 35/75 than at 29/50 and 29/75. These results suggest that humid heat exposure during night sleep increases the thermal load to supress the sleep-evoked Tr decrease, stage 3, SWS, and REM, and increase wakefulness.     

A two‐part,double‐blind,placebo‐controlled trial of exogenous melatonin in REM sleep behaviour disorder

Rapid eye movement (REM) sleep behaviour disorder (RBD) has been suggested to predict the development of neurodegenerative disorders. Patients with RBD are acting out dream behaviour associated with loss of normal muscle atonia of REM sleep. The aim of the present study was to confirm that exogenous melatonin improves RBD. Eight consecutively recruited males (mean age 54 years) with a polysomnographically (PSG) confirmed diagnosis of RBD were included in a two‐part, randomized, double‐blind, placebo‐controlled cross‐over study. Patients received placebo and 3 mg of melatonin daily in a cross‐over design, administered between 22:00 h and 23:00 h over a period of 4 weeks. PSG recordings were performed in all patients at baseline, at the end of Part I of the trial and at the end of Part II of the trial. Compared to baseline, melatonin significantly reduced the number of 30‐s REM sleep epochs without muscle atonia (39% versus 27%; P = 0.012), and led to a significant improvement in clinical global impression (CGI: 6.1 versus 4.6; P = 0.024). Interestingly, the number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I (–16% compared to baseline; P = 0.043). In contrast, patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (i.e. during melatonin treatment). The data suggest that melatonin might be a second useful agent besides clonazepam in the treatment of RBD.     

Different criteria of sleep latency and the effect of melatonin on sleep consolidation

OBJECTIVES: Since there is no consensus definition of sleep onset, we studied different aspects of initial sleep periods in healthy volunteers taking melatonin. Two criteria for sleep latency were used: 10 minutes of uninterrupted sleep and 1.5 minutes of stage 1 sleep. PARTICIPANTS: Forty healthy male volunteers (mean age 28 +/- 5 years) were assigned to 2 groups: 30 ingested melatonin and 10 placebo. DESIGN: All volunteers underwent an initial polysomnogram (baseline) after a 1-night adaptation period. The next day, the placebo or a 10-mg dose of melatonin was administered for 28 days, 1 hour before sleep time, in double-blind fashion. The second polysomnogram was recorded on day 14. SETTING: Sleep laboratory RESULTS: Chronic melatonin administration led to a significant reduction in sleep latency, using only the criterion 10 minutes of uninterrupted sleep. This effect suggests that melatonin may have a hypnotic effect, and the use of melatonin may lead to better sleep consolidation. CONCLUSIONS: These results show differences that have clinical implications, since the criteria used to diagnose initial insomnia were based on sleep onset.     

Changes in sleepiness and body temperature precede nocturnal sleep onset: Evidence from a polysomnographic study in young men

Recent research has shown a close temporal relationship between the nocturnal decrease in rectal core temperature and the initiation of sleep. However, there is not yet a clear temporal relationship between changes in peripheral and core temperatures and nocturnal sleep onset. We recorded body temperatures in 14 adult males (age±SEM=22.1±0.6 y), who attended the sleep laboratory for an adaptation night and two counterbalanced experimental sessions. Subjects self-selected lights-out on one experimental night (the Habitual Sleep condition). To determine the relationship between body temperature changes and sleep onset, lights out was delayed until after 01.00 hours on the other experimental night (Delayed Sleep condition). Individual datasets in both conditions were expressed relative to the time of sleep onset in the Habitual Sleep condition only, so that they were aligned at identical clock times. Saliva samples confirmed that mean dim light melatonin onset (DLMO) occurred at 00.10±00.16 hours in the Delayed Sleep condition, which was after habitual sleep onset at 23.44±00.08 hours. Rectal core temperature (Tc) decreased significantly over time only in the Habitual Sleep condition ( P < 0.01). For the 20 min before habitual sleep onset, Delayed Sleep Tc was on average 0.1°C higher than Tc in the Habitual Sleep condition ( P < 0.01). The greater decline in Habitual Sleep Tc was associated with significantly increased peripheral hand and foot skin temperatures before sleep (both P < 0.05). Subjective sleepiness measures were higher in the Habitual Sleep onset condition from 150 min prior until sleep onset ( P < 0.01). From these results it is reasonable to infer that a sequence of thermoregulatory and sleep propensity changes occur before, but are associated with habitual sleep onset, as the changes are significantly attenuated if sleep is delayed.     

Influence on human sleep patterns of lowering and delaying the minimum core body temperature by slow changes in the thermal environment

STUDY OBJECTIVES: We hypothesized that appropriate changes in thermal environment would enhance the quality of sleep. DESIGN/SETTING: Controlled laboratory study. PARTICIPANTS: Healthy young men (n = 7, mean age 26 years). INTERVENTIONS: Nocturnal sleep structures in semi-nude subjects were compared between a condition where an ambient temperature (Ta) of 29.5 degree C was maintained throughout the night (constant Ta), and a second condition (dynamic Ta) where Ta changed slowly within the thermoneutral range (from 27.5 C to 29.5 degree C). MEASUREMENTS AND RESULTS: Statistically significant (P < 0.05) results included a lower and a later occurrence of minimum core body temperature (Tc), and a longer duration of slow-wave (stages 3+4) sleep in dynamic versus constant T. However, total sleep time, sleep efficiency, the total durations of light (stages 1+2) and rapid eye movement sleep, and the latencies to sleep onset, slow-wave sleep, and rapid eye movement sleep did not differ between conditions. CONCLUSIONS: Lowering the minimum and delaying the nadir of nocturnal Tc increases slow-wave sleep (probably by an increase of dry heat loss); use of this tactic might improve the overall quality of sleep.     

Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia

Research has shown efficacy of melatonin treatment to advance sleep-wake rhythms in insomnia. In healthy adults, direction and magnitude of the phase shift depends on the timing of administration relative to the phase position of the circadian system. Therefore, in the present study we investigated whether in children with chronic sleep onset insomnia (SOI) efficacy of melatonin treatment in the early evening could be predicted from dim light melatonin onset (DLMO), a phase marker of the circadian system. We combined data of two previously published double blind, randomized, placebo-controlled trials in 110 participants, aged 6-12 years. Sleep was actigraphically estimated, and saliva collected, at baseline and in the third week of a 4-week treatment period with 5 mg melatonin or placebo at 18:00 or 19:00 hours. Primary outcome measures were pre- to post-treatment changes in dim light melatonin onset (DeltaDLMO), sleep onset (DeltaSO), sleep latency (DeltaSL), and total sleep duration (DeltaTSD). Melatonin advanced DLMO with +1:12 h (P < 0.001), SO with +0:42 h (P = 0.004), SL decreased with 25 min (P = 0.019), and TSD did not change significantly, as compared with placebo. In the melatonin-treated group, but not in the placebo-treated group, pretreatment DLMO was significantly related to DeltaDLMO [F(1, 29) = 7.28, P = 0.012] and DeltaSO [F(1, 25) = 7.72, P = 0.010]. The time interval between treatment administration and pretreatment DLMO (INT) was only significantly related to DeltaSO [F(1,26) = 5.40, P = 0.028]. The results suggest that in children with SOI, the efficacy of early evening melatonin to advance sleep onset and endogenous melatonin onset increases the later the pretreatment DLMO is.     

The 24-h growth hormone rhythm in men: sleep and circadian influences questioned

The 24-h rhythm of growth hormone (GH) is thought to be controlled primarily by sleep processes with a weak circadian component. This concept has been recently questioned in sleep-deprived persons. To test the notion of a high sleep-dependency of GH release, we established simultaneous 24-h rhythms of GH and melatonin, a circadian marker, in night workers who form a model for challenging sleep and circadian processes. Ten day-active subjects and 11 night workers were studied during their usual sleep-wake schedule, with sleep from 23:00 to 07:00 hours and 07:00 to 15:00 hours, respectively. Experiments were conducted in sleep rooms under continuous nutrition, bed rest, and dim light. Melatonin and GH were measured every 10 min over 24 h. In day-active subjects, melatonin and GH showed the well-known 24-h profiles, with a major sleep-related GH pulse accounting for 52.8 +/- 3.5% of the 24-h GH production and the onset of the melatonin surge occurring at 21:53 hours +/- 18 min. In night workers, melatonin showed variable circadian adaptation, with the onset of secretion varying between 21:45 and 05:05 hours. The sleep-related GH pulse was lowered, but the reduction was compensated for by the emergence of large individual pulses occurring unpredictably during waking periods, so that the total amount of GH secreted during the 24 h was constant. One cannot predict the degree of GH adaptation from the highly variable melatonin shift. These results argue against the concept that sleep processes exert a predominant influence on GH release whatever the conditions. When sleep and circadian processes are misaligned, the blunting of the sleep-related GH pulse is counteracted, as in sleep-deprived persons, by a compensatory mechanism promoting GH pulses during wakefulness.     

Endogenous Melatonin is Not Obligatory for the Regulation of the Rat Sleep-Wake Cycle

Study Objectives:

Though melatonin and melatonin receptor agonists are in clinical use and under development for treating insomnia, the role of endogenous melatonin in the regulation of the sleep-wake cycle remains uncertain. Some clinical case reports suggest that reduced nocturnal melatonin secretion is linked to sleep disruption, but pineal-gland removal in experimental animals has given variable results.

Design:

The present study examined the effects of pinealectomy on the diurnal sleep-wake cycle of rats implanted with a radiotransmitter to allow continuous measurement of cortical electroencephalogram, electromyogram, and core temperature (Tc) without restraint in their home cages.

Measurements and Results:

Tc was slightly (0.2°C) but significantly lower after pineal removal. The total amount and diurnal distribution of locomotor activity, wake, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were unaltered in pinealectomized rats compared to sham-operated controls. Sleep consolidation measured by determining wake, NREM sleep, and REM sleep bout length and frequency was also unchanged. The EEG power spectrum during NREM sleep was unchanged, but a significant decrease in theta power (5-8 Hz) during REM sleep episodes was found.

Conclusions:

Our data provide no evidence that endogenous circulating melatonin plays a role in regulating the sleep-wake cycle in rats. However, because cortical theta oscillations are generated in the CA1-3 layer of the hippocampus, neurons known to express melatonin receptors, this suggests that a lack of melatonin following pineal removal influences the function of these neurons and is consistent with previous work suggesting that endogenous melatonin is an important regulator of hippocampal physiology.

Citation:

Fisher SP; Sugden D. Endogenous melatonin is not obligatory for the regulation of the rat sleep-wake cycle. SLEEP 2010;33(6):833-840.     

Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol

STUDY OBJECTIVES: To compare residual effects of zaleplon 10 mg, zopiclone 7.5 mg, and placebo, and a social dose of alcohol on car driving, memory, and psychomotor performance. DESIGN: Two-part placebo controlled, crossover study. Part 1 was single blind, Part 2 double blind. SETTING: University research institute. PARTICIPANTS: Thirty healthy volunteers (15 men and 15 women, mean age 32 +/- 7 years) INTERVENTIONS: In Part 1 alcohol and alcohol-placebo drinks were administered around noon. In Part 2 single oral doses of zaleplon 10 mg, zopiclone 7.5 mg and placebo were administered at bedtime. MEASUREMENT AND RESULTS: A highway driving test, laboratory tests of word learning, critical tracking and divided attention, and subjective assessments of sleep, mood, and effects of treatments on driving. Driving started 40 minutes after a second alcohol dose in Part 1, and 10 hours after drug intake in Part 2. The results demonstrated that alcohol, at average plasma concentrations of approximately 0.030 g/dl, significantly impaired performance in all tests. Zaleplon's residual effects did not differ significantly from those of placebo in any test. In contrast, zopiclone had significant residual effects on driving, divided attention, and memory. The magnitude of impairment in the driving test observed the morning after zopiclone 7.5 mg was twice that observed with alcohol. CONCLUSION: Zaleplon 10 mg has no residual effects on driving when taken at bedtime, 10 hours before driving. In contrast, zopiclone 7.5 mg can cause marked residual impairment. Patients should be advised to avoid driving the morning after zopiclone administration.     

Attenuated thermoregulatory response to mild thermal challenge in subjects with sleep-onset insomnia

STUDY OBJECTIVES: To determine if heat loss capacity of sleep onset insomniacs was different from that of healthy sleepers. DESIGN: Measure skin temperature responses following brief exposure to a warm peripheral thermal challenge (PTC). SETTING: Sleep research laboratory in South Australia. PARTICIPANTS: Eight primary insomniacs with sleep onset insomnia according to DSM-IV-TR criteria (SOI; 5 male, 3 female; mean age +/- SEM = 35.2 +/- 4.2 years) and ten healthy sleeping control subjects (HS; 7 male, 3 female; mean age = 28.2 +/- 2.8 years). INTERVENTIONS: Two PTC conditions in counterbalanced order on non-consecutive days. During each condition, the subject's non-dominant forearm and hand were immersed for 3 minutes in Warm (45 degrees C) or Control water (i.e. same as the subject's non-dominant index finger temperature just prior to immersion, range 30-35 degrees C). MEASUREMENTS AND RESULTS: HS had a significantly higher maximum finger temperature response after immersion than SOI (P < 0.05). Expressed relative to Control PTC temperatures, the Warm PTC caused a significant increase in mean finger temperature for HS of 4.1 +/- 0.8 degrees C, compared with SOI of 0.9 +/- 0.4 degrees C. A significant negative relationship was observed between maximum finger temperature response and self-reported sleep onset latencies (R = -0.57, P < 0.05). There were no main effects of sleep status (SOI vs. HS) or interactions by time, in skin temperatures measured at either the back of hands or feet. CONCLUSIONS: SOI were observed to have significantly attenuated thermoregulatory responses to a mild positive thermal challenge, providing evidence that impaired heat loss capacity from the periphery is associated with sleep onset insomnia.     

Sleep-stabilizing effects of E-6199, compared to zopiclone, zolpidem and THIP in mice

Gamma aminobutyric acid (GABA)A receptor modulators constitute the majority of clinically used sedative-hypnotics. These compounds have the capacity to initiate and maintain sleep, but decrease REM sleep and delta activity within NREM sleep. In order to avoid such sleep adverse effects, the development of novel compounds remains of interest. STUDY OBJECTIVES: The present study aimed at characterizing the acute effects of a novel putative hypnotic compound, E-6199, compared to zopiclone, zolpidem, and THIP on sleep-wakefulness patterns in mice. We also investigated whether repeated administration (daily injection during 10 days) of E-6199 was associated with tolerance and sleep disturbances at cessation of treatment. MEASUREMENTS AND RESULTS: Polygraphic recordings were performed during 8 h after acute treatment with the various compounds. Under such conditions, E-6199 (5-20 mg/kg i.p.), zopiclone and zolpidem (2-10 mg/kg i.p.), but not THIP (2-10 mg/kg i.p.), exerted a marked sleep-promoting effect. Furthermore, E-6199 specifically increased the duration of NREM and markedly improved sleep continuity by lengthening NREM sleep episodes and reducing short awakenings and microarousal frequency. It also intensified NREM sleep by enhancing the slow wave activity within NREM at wake-NREM transitions. These effects were sustained and became even larger during chronic administration. Finally, abrupt E-6199 withdrawal did not elicit negative sleep effects. CONCLUSIONS: Our findings demonstrate that E-6199 may be an effective hypnotic compound that promotes and improves NREMS, without producing EEG side effects, tolerance or withdrawal phenomena, when administered under chronic conditions.     

Sleeping with an electric blanket: effects on core temperature, sleep, and melatonin in young adults.

Previous studies have inferred a relationship between core temperature and sleep disruption from manipulations of core temperature such as heating prior to sleep or administration of hyperthermic substances. To examine the relationship more directly, this study aimed to produce a direct increase in core temperature during the sleep period. Following an adaptation night, 16 subjects underwent counter-balanced baseline and experimental conditions, on non-consecutive nights between 1900 and 0800h. In the experimental condition, subjects were heated between 0230h and wake up, which significantly increased mean core temperature from baseline levels between 0400 and 0700h by 0.18 +/- 0.03 degree C (mean +/- SEM, p < 0.05). This increase in core temperature was associated with a significant decrease in sleep efficiency between 0330 and 0730h of 5.5 +/- 0.9% (mean +/- SD, p < 0.05). Polysomnographic measures indicated a significant increase in the number of stage changes and the amounts of stage 0 and stage 1 sleep (p < 0.05). Other stages of sleep and the number and duration of arousals were not significantly effected by heating. There was a strong trend toward and increase in the number of arousals (p = 0.054), however, core body temperature did not increase across arousals. Also, melatonin output was not effected by heating. Taken together, these results suggest that increased nocturnal core temperature alone may disrupt sleep. Additionally, the results support evidence suggesting that the circadian regulation of the sleep/wake cycle may be mediated via core temperature.