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Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish.

ABSTRACT: In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep-wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr-/-). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indicating conservation of the excitatory phenotype. Visualization of the entire HCRT circuit in zebrafish stably expressing hcrt:EGFP revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where hcrtr mRNA is expressed. As pineal-produced melatonin is a major sleep-inducing hormone in zebrafish, we further studied how the HCRT and melatonin systems interact functionally. mRNA level of arylalkylamine-N-acetyltransferase (AANAT2), a key enzyme of melatonin synthesis, is reduced in hcrtr-/- pineal gland during the night. Moreover, HCRT perfusion of cultured zebrafish pineal glands induces melatonin release. Together these data indicate that HCRT can modulate melatonin production at night. Furthermore, hcrtr-/- fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in hcrtr-/- fish, but not in the wild-type siblings. These results demonstrate the existence of a functional HCRT neurons-pineal gland circuit able to modulate melatonin production and sleep consolidation.

SUBMITTER: Appelbaum L

PROVIDER: S-EPMC2799794 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish.

Appelbaum Lior L Wang Gordon X GX Maro Geraldine S GS Mori Rotem R Tovin Adi A Marin Wilfredo W Yokogawa Tohei T Kawakami Koichi K Smith Stephen J SJ Gothilf Yoav Y Mignot Emmanuel E Mourrain Philippe P

Proceedings of the National Academy of Sciences of the United States of America 20091204 51

In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep-wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr-/-). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indica ...[more]

PMID: 19966231

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Project description:BackgroundDelayed Sleep-Wake Phase Disorder (DSWPD) is characterised by sleep initiation insomnia when attempting sleep at conventional times and difficulty waking at the required time for daytime commitments. Although there are published therapeutic guidelines for the administration of melatonin for DSWPD, to our knowledge, randomised controlled trials are lacking. This trial tested the efficacy of 0.5 mg melatonin, combined with behavioural sleep-wake scheduling, for improving sleep initiation in clinically diagnosed DSWPD patients with a delayed endogenous melatonin rhythm relative to patient-desired (or -required) bedtime (DBT).MethodsThis randomised, placebo-controlled, double-blind clinical trial was conducted in an Australian outpatient DSWPD population. Following 1-wk baseline, clinically diagnosed DSWPD patients with delayed melatonin rhythm relative to DBT (salivary dim light melatonin onset [DLMO] after or within 30 min before DBT) were randomised to 4-wk treatment with 0.5 mg fast-release melatonin or placebo 1 h before DBT for at least 5 consecutive nights per week. All patients received behavioural sleep-wake scheduling, consisting of bedtime scheduled at DBT. The primary outcome was actigraphic sleep onset time. Secondary outcomes were sleep efficiency in the first third of time in bed (SE T1) on treatment nights, subjective sleep-related daytime impairment (Patient Reported Outcomes Measurement Information System [PROMIS]), PROMIS sleep disturbance, measures of daytime sleepiness, clinician-rated change in illness severity, and DLMO time.FindingsBetween September 13, 2012 and September 1, 2014, 307 participants were registered; 116 were randomised to treatment (intention-to-treat n = 116; n = 62 males; mean age, 29.0 y). Relative to baseline and compared to placebo, sleep onset occurred 34 min earlier (95% confidence interval [CI] -60 to -8) in the melatonin group. SE T1 increased; PROMIS sleep-related impairment, PROMIS sleep disturbance, insomnia severity, and functional disability decreased; and a greater proportion of patients showed more than minimal clinician-rated improvement following melatonin treatment (52.8%) compared to placebo (24.0%) (P < 0.05). The groups did not differ in the number of nights treatment was taken per protocol. Post-treatment DLMO assessed in a subset of patients (n = 43) was not significantly different between groups. Adverse events included light-headedness, daytime sleepiness, and decreased libido, although rates were similar between treatment groups. The clinical benefits or safety of melatonin with long-term treatment were not assessed, and it remains unknown whether the same treatment regime would benefit patients experiencing DSWPD sleep symptomology without a delay in the endogenous melatonin rhythm.ConclusionsIn this study, melatonin treatment 1 h prior to DBT combined with behavioural sleep-wake scheduling was efficacious for improving objective and subjective measures of sleep disturbances and sleep-related impairments in DSWPD patients with delayed circadian phase relative to DBT. Improvements were achieved largely through the sleep-promoting effects of melatonin, combined with behavioural sleep-wake scheduling.Trial registrationThis trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000425897.

Project description:Delayed sleep-wake phase disorder (DSPD) is the most frequently occurring intrinsic circadian rhythm sleep-wake disorder, with the highest prevalence in adolescence. Melatonin is the first-choice drug treatment. However, to date melatonin (in a controlled-release formulation) is only authorised for the treatment of insomnia in children with autism or Smiths-Magenis syndrome. Concerns have been raised with respect to the safety and efficacy of melatonin for more general use in children, as melatonin has not undergone the formal safety testing required for a new drug, especially long-term safety in children. Melatonin is known to have profound effects on the reproductive systems of rodents, sheep and primates, as well as effects on the cardiovascular, immune and metabolic systems. The objective of the present article was therefore to establish the efficacy and safety of exogenous melatonin for use in children with DSPD, based on in vitro, animal model and clinical studies by reviewing the relevant literature in the Medline database using PubMed. Acute toxicity studies in rats and mice showed toxic effects only at extremely high melatonin doses (>400 mg/kg), some tens of thousands of times more than the recommended dose of 3-6 mg in a person weighing 70 kg. Longer-term administration of melatonin improved the general health and survival of ageing rats or mice. A full range of in vitro/in vivo genotoxicity tests consistently found no evidence that melatonin is genotoxic. Similarly long term administration of melatonin in rats or mice did not have carcinogenic effects, or negative effects on cardiovascular, endocrine and reproductive systems. With regard to clinical studies, in 19 randomised controlled trials comprising 841 children and adolescents with DSPD, melatonin treatment (usually of 4 weeks duration) consistently improved sleep latency by 22-60 min, without any serious adverse effects. Similarly, 17 randomised controlled trials, comprising 1374 children and adolescents, supplementing melatonin for indications other than DSPD, reported no relevant adverse effects. In addition, 4 long-term safety studies (1.0-10.8 yr) supplementing exogenous melatonin found no substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores. Finally, post-marketing data for an immediate-release melatonin formulation (Bio-melatonin), used in the UK since 2008 as an unlicensed medicine for sleep disturbance in children, recorded no adverse events to date on sales of approximately 600,000 packs, equivalent to some 35 million individual 3 mg tablet doses (MHRA yellow card adverse event recording scheme). In conclusion, evidence has been provided that melatonin is an efficacious and safe chronobiotic drug for the treatment of DSPD in children, provided that it is administered at the correct time (3-5 h before endogenous melatonin starts to rise in dim light (DLMO)), and in the correct (minimal effective) dose. As the status of circadian rhythmicity may change during long-time treatment, it is recommended to stop melatonin treatment at least once a year (preferably during the summer holidays).

Dataset Information

Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish.

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Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish.

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