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We examined whether a polymorphism of the PERIOD3 gene (PER3; rs57875989) modulated the sleep‐promoting effects of melatonin in Delayed Sleep‐Wake Phase Disorder (DSWPD). One hundred and four individuals (53 males; 29.4 ±10.0 years) with DSWPD and a delayed dim light melatonin onset (DLMO) collected buccal swabs for genotyping (PER34/4 n = 43; PER3 5 allele [heterozygous and homozygous] n = 60). Participants were randomised to placebo or 0.5 mg melatonin taken 1 hour before desired bedtime (or ~1.45 hours before DLMO), with sleep attempted at desired bedtime (4 weeks; 5‐7 nights/week). We assessed sleep (diary and actigraphy), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Patient‐Reported Outcomes Measurement Information System (PROMIS: Sleep Disturbance, Sleep‐Related Impairment), Sheehan Disability Scale (SDS) and Patient‐ and Clinician‐Global Improvement (PGI‐C, CGI‐C). Melatonin treatment response on actigraphic sleep onset time did not differ between genotypes. For PER34/4 carriers, self‐reported sleep onset time was advanced by a larger amount and sleep onset latency (SOL) was shorter in melatonin‐treated patients compared to those receiving placebo (P =.008), while actigraphic sleep efficiency in the first third of the sleep episode (SE T1) did not differ. For PER3 5 carriers, actigraphic SOL and SE T1 showed a larger improvement with melatonin (P <.001). Melatonin improved ISI (P =.005), PROMIS sleep disturbance (P <.001) and sleep‐related impairment (P =.017), SDS (P =.019), PGI‐C (P =.028) and CGI‐C (P =.016) in PER34/4 individuals only. Melatonin did not advance circadian phase. Overall, PER34/4 DSWPD patients have a greater response to melatonin treatment. PER3 genotyping may therefore improve DSWPD patient outcomes. [ABSTRACT FROM AUTHOR]

Gilbert, Saul S., Helen J. Burgess, David J. Kennaway, and Drew Dawson. Attenuation of sleep propensity, core hypothermia, and peripheral heat loss after temazepam tolerance. Am J Physiol Regulatory Integrative Comp Physiol 279: R1980-R1987, 2000.--If changes in thermoregulation mediate sleepiness induced by sedative/hypnotics, then a reduction in the soporific efficacy (tolerance) of these agents may be accompanied by a concomitant reduction in their thermoregulatory effects. We compared the thermoregulatory and soporific effects of acute temazepam (30 mg at 1400) in 11 young male subjects before and immediately after 7 consecutive days of temazepam (30 mg). Subjects lay supine (0800-2030), while foot ([T.sub.ft]) and rectal ([T.sub.c]) temperatures were recorded. Sleep onset latency (SOL) was measured hourly using 20-min multiple sleep latency tests. Relative to placebo, temazepam significantly reduced both [T.sub.c] and SOL (-0.31 [degrees] C and 14.1 min) while increasing [T.sub.ft] (3.39 [degrees] C). A significant tolerance developed after the week of temazepam, with a mean reduction in soporific efficacy of 4.0 [+ or -] 0.8 min. This was accompanied by a concomitant attenuation in both [T.sub.c] (-0.16 [degrees] C) and [T.sub.ft] (1.44 [degrees] C). Furthermore, SOL was temporally related to [T.sub.ft] and the maximum rate of decline in [T.sub.c] before and after tolerance. Together, these results indicate that the thermoregulatory system may be functionally involved in the regulation of sleepiness. heart rate; multiple sleep latency test; human male

Firth, Bruce T., Ingrid Belan, David J. Kennaway, and Robert W. Moyer. Thermocyclic entrainment of lizard blood plasma melatonin rhythms in constant and cyclic photic environments. Am. J. Physiol. 277 (Regulatory Integrative Comp. Physiol. 46): R1620-R1626, 1999.--We assessed how chronic exposure to 6-h cryophase temperatures of 15 [degrees] C in an otherwise 33 [degrees] C environment entrains the rhythm of blood plasma melatonin rhythms in lizards (Tiliqua rugosa) subjected to constant dark (DD), constant light (LL), and to 12:12-h light-dark cycles (12L:12D). The peak of the melatonin rhythm was entrained by the cryophase temperature of the thermocycle in DD and LL, irrespective of the time at which the cryophase temperature was applied. Comparable thermocycles of 6 h at 15 [degrees] C imposed on a 12L:12D photocycle, however, affected the amplitude and phase of the melatonin rhythm, depending on the phase relationship between light and temperature. Cold pulses in the early light period and at midday resulted, respectively, either in low amplitude or nonexistent melatonin rhythms, whereas those centered in or around the dark phase elicited rhythms of high amplitude. Supplementary experiments in 12L:12D using two intermittent 6-h 15 [degrees] C cryophases, one delivered in the midscotophase and another in the midphotophase, elicited melatonin rhythms comparable to those in lizards subjected to constant 33 [degrees] C and 12L:12D. In contrast, lizards subjected to 12L:12D and a 33 [degrees] C: 15 [degrees] C thermocycle, whose thermophase was aligned with the photophase, produced a threefold increase in the amplitude of the melatonin rhythm. Taken together, these results support the notion that there is an interaction between the external light and temperature cycle and a circadian clock in determining melatonin rhythms in Tiliqua rugosa. thermoperiodism; cryophase temperature; circadian oscillator; phase shift

Ferguson, Sally A., and David J. Kennaway. Emergence of altered circadian timing in a cholinergically supersensitive rat line. Am. J. Physiol. 277 (Regulatory Integrative Comp. Physiol. 46): R1171-R1178, 1999.--Mammalian circadian rhythms are controlled by the suprachiasmatic nuclei (SCN) in concert with light information. Several neurotransmitters and neural pathways modulate light effects on SCN timing. This study used a line of rat with an upregulated cholinergic system to investigate the role of acetylcholine in rhythmicity. With the use of a selective breeding program based on the thermic response to a cholinergic agonist, we developed a supersensitive ([S.sub.ox]) and subsensitive ([R.sub.ox]) rat line. The [S.sub.ox] rats showed an earlier onset time of melatonin rhythm under a 12:12-h light-dark photoperiod from generation 3 (3 [+ or -] 0.5 h after dark) compared with [R.sub.ox] rats (4.5 [+ or -] 0.1 h) and an earlier morning decline in temperature (0.9 [+ or -] 0.3 h before lights on) compared with [R.sub.ox] animals (0.1 [+ or -] 0.1 h). Furthermore, the [S.sub.ox] animals displayed a significantly shorter free-running period of temperature rhythm than [R.sub.ox] rats (23.9 [+ or -] 0.04 and 24.3 [+ or -] 0.1 h, respectively, P [is less than] 0.05). The results suggest that the altered circadian timing of the [S.sub.ox] rats may be related to the cholinergic supersensitivity, intimating a role for acetylcholine in the circadian timing system. suprachiasmatic nucleus; oxotremorine; melatonin

Melatonin has been proposed as a potent anti-oxidant, and its presence in many plants and foods has been suggested to be beneficial for health. Indeed, the concentrations of melatonin in blood and the melatonin metabolite 6 sulphatoxymelatonin in urine have been found to increase significantly after ingestion of melatonin-rich foods. In this review, the studies have been critically evaluated in light of the reported plant melatonin concentrations and our knowledge of pharmacokinetics of orally administered pure melatonin. In the case of studies involving measurement of plasma melatonin following ingestion of beer or fruits, the reported increase in melatonin is not consistent with the amount of melatonin ingested. Similarly, the amount of melatonin metabolite excreted following ingestion of melatonin-rich foods greatly exceeded the amount of melatonin ingested. It is concluded that studies reporting the appearance of melatonin in blood and its metabolites in urine following ingestion of melatonin-rich foods are flawed. While there may be health benefits for certain foods, it is difficult to accept that these are due to their low melatonin content. [ABSTRACT FROM PUBLISHER]

Shiftworkers have impaired performance when driving at night and they also alter their eating patterns during nightshifts. However, it is unknown whether driving at night is influenced by the timing of eating. This study aims to explore the effects of timing of eating on simulated driving performance across four simulated nightshifts. Healthy, non-shiftworking males aged 18–35 years (n= 10) were allocated to either an eating at night (n= 5) or no eating at night (n= 5) condition. During the simulated nightshifts at 1730, 2030 and 0300 h, participants performed a 40-min driving simulation, 3-min Psychomotor Vigilance Task (PVT-B), and recorded their ratings of sleepiness on a subjective scale. Participants had a 6-h sleep opportunity during the day (1000–1600 h). Total 24-h food intake was consistent across groups; however, those in the eating at night condition ate a large meal (30% of 24-h intake) during the nightshift at 0130 h. It was found that participants in both conditions experienced increased sleepiness and PVT-B impairments at 0300 h compared to 1730 and 2030 h (p< 0.001). Further, at 0300 h, those in the eating condition displayed a significant decrease in time spent in the safe zone (p< 0.05; percentage of time within 10 km/h of the speed limit and 0.8 m of the centre of the lane) and significant increases in speed variability (p< 0.001), subjective sleepiness (p< 0.01) and number of crashes (p< 0.01) compared to those in the no eating condition. Results suggest that, for optimal performance, shiftworkers should consider restricting food intake during the night. [ABSTRACT FROM AUTHOR]

Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesity. [ABSTRACT FROM AUTHOR]