Circadian rhythm sleep melatonin

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002 Pandi-Perumal et al. 2005, 2006 Srinivasan et al. 2005a,b, 2006 Hardeland et al. 2006). 

Zhdanova, I. V. Tucci, V. (2003). Melatonin, circadian rhythms, and sleep. Curr. 

To mimic melatonin action and increase the half-life is the goal of melatonin receptor agonists, which are the more recent addition to the insomnia therapeutic armamentarium. These compounds, in addition to use for insomnia, may have potential application in the synchronization of disturbed circadian rhythms, sleep disturbances in the elderly, seasonal depression and jet lag, to name a few. Furthermore, studies have shown that melatonin receptor agonists do not induce any of the hypothermic, hypotensive or bradycardic effects caused by melatonin in humans [27,28]. 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Ramelteon (Rozerem). Recently approved by the FDA for treatment of insomnia in the US, ramelteon acts via a completely novel mechanism of action, that is, stimulating so-called melatonin Ti and T2 receptors in the brain s suprachiasmatic nucleus (SCN). The SCN is regarded as the body s master clock that regulates the sleep-wake cycle and other circadian rhythms. The effects of ramelteon in some respects mimic those of melatonin. Ramelteon, in clinical trials, administered at bedtime doses of 8 mg, outperformed placebo with respect to several indices of sleep disturbance (see Table 9.4). 

Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle (see Chapter 16). Ramelteon, a novel hypnotic drug prescribed specifically for patients who have difficulty in falling asleep, is an agonist at MTX and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain. 

Melatonin is an endogenous neurohormone that is produced primarily by the pineal gland. In humans, melatonin is normally released at night, with plasma levels tending to peak between 2 and 4 AM.47 Melatonin is associated with the ability to regulate sleep-wake cycles, and perhaps other circadian rhythms.3,31 Because of this effect, synthetic melatonin supplements have been used primarily to treat insomnia, especially in individuals with disturbed sleep cycles or persons who are blind and cannot regulate melatonin release because they are unable to respond visually to normal light-dark cycles.3... 

The hormone melatonin is involved in the control of the circadian system, and has been implicated in the control of sleep [64], Several studies have examined the effectiveness of melatonin as a treatment of insomnia. While some researchers have reported a positive effect [65, 66], others have reported little or no effect [67,68], At present, the magnitude of beneficial effects following melatonin administration to insomniacs is unclear. Furthermore, the mechanism of action of this hormone with relation to sleep initiation, has not yet been fully described [69], Finally, exposure to bright light therapy during the early morning hours has been reported to relieve sleep onset insomnia, even in elderly patients [70], This may be due to the restoration of circadian rhythms in these insomniacs. 

Cajochen C, Krauchi K, Wirz-Justice A (2003) Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinal 15 432-437... 

Czeisler CA, Cajochen C, Turek FW. Melatonin in the regulation of sleep and circadian rhythms. In Principles and Practice of Sleep Medicine, 3rd ed., WB Saunders, 2000, Philadelphia,... 

It seems very likely that there are important advances to be made in the application of melatonin agonists to the modification of sleep states and circadian rhythms. See also MELATONIN RECEPTOR ANTAGONISTS. 

The permissive serotonin hypothesis proposes that serotonin (5-hydroxytryptamine or 5-HT) plays a critical role in modulating brain activity (e.g., stabilization of the catecholamine system and inhibition of dopamine [DA] release), and is low in both mania and depression. L-tryptophan or 5-HT deficiency and changes in the light-dark cycle may result in reduced melatonin secretion from the pineal gland that disrupts the sleep-wake cycle, alters circadian rhythms, and causes seasonal affective changes. ... 

Melatonin has been used to regulate the sleep-wake cycle and is used often to treat insomnia. It is not recommended during pregnancy and breast-feeding becanse of a lack of information abont its safety. Lower doses of melatonin (e.g., 0.1-1 mg at bedtime) are effective in initiating sleep higher doses may not improve the hypnotic effect. The rednction in daytime snnUght, which increases melatonin secretion, may exacerbate PMS in the winter this type of seasonal mood disorder may respond to phototherapy. Early sleep deprivation also may help to correct circadian rhythm disturbances in PMDD. ... 

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