Melatonin cycle

Naturally Occurring Compounds. Many derivatives of iadole are found ia plants and animals where they are derived from the amino acid tryptophan. Several of these have important biological function or activity. Serotonin [50-67-9] (12) functions as a neurotransmitter and vasoconstrictor (35). Melatonin [73-31-4] (13) production is controlled daily by the circadian cycle and its physiological level iafluences, and seasonal rhythms ia humans and other species (36). Indole-3-acetic acid [87-51-4] (14) is a plant growth stimulant used ia several horticultural appHcations (37). 

Figure 22.1 Pathways projecting to and from the suprachiasmatic nucleus (SCN). Inputs from photoreceptors in the retina help to reset the circadian clock in response to changes in the light cycle. Other inputs derive from the lateral geniculate complex and the serotonergic, Raphe nuclei and help to reset the SCN in response to non-photic stimuli. Neurons in the SCN project to the hypothalamus, which has a key role in the regulation of the reproductive cycle, mood and the sleep-waking cycle. These neurons also project to the pineal gland which shows rhythmic changes in the rate of synthesis and release of the hormone, melatonin...

The rate of melatonin synthesis is controlled primarily by the release of noradrenaline from sympathetic fibres originating in the superior cervical ganglion. The activity of these neurons and, consequently, the synthesis and release of melatonin, follows a circadian rhythm such that sympathetic input and melatonin synthesis are both increased in the dark. This coupling with the light cycle certainly involves the SCN since destruction of this nucleus greatly reduces the fluctuations in melatonin production. Moreover, retrograde transneural tracing has shown that there is a neuronal pathway... 

The precise role of melatonin in sleep and waking is uncertain but it seems to act as a go-between for the light and biological cycles and evidence suggests that it has a reciprocal relationship with the SCN (Fig. 22.3). Its actions are mediated by (MLi) receptors which are found predominantly in the SCN as well as thalamic nuclei and the anterior pituitary. These are G protein-coupled receptors, with seven transmembrane domains, that inhibit adenylyl cyclase. Their activation by melatonin, or an MLi agonist such as 2-iodomelatonin, restores the impaired circadian cycle in aged rats. 

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). 

The circadian pattern of pineal NAT activity and consequently melatonin secretion is controlled by the suprachiasmatic nuclei (SCN) as it is abolished by lesions of the SCN, the major circadian oscillator (Klein and Moore 1979). Thus, the environmental L/D cycle acts as the pervasive and pre-eminent Zeitgeber that regulates melatonin synthesis (Scheer and Czeisler 2005). 

One of us examined the timely use of three factors (melatonin treatment, exposure to light, physical exercise) to hasten the resynchronization of the sleep-wake cycle in a group of elite sports competitors after a transmeridian flight across 12 time zones (Cardinali et al. 2002). Outdoor light exposure and physical exercise were used to cover symmetrically the phase delay and the phase advance portions of the phase-response curve. Melatonin taken at local bedtime helped to resynchronize the circadian oscillator to the new time. Individual actograms taken from sleep log data showed that all subjects became synchronized in their sleep to the local time in 24-48 h, well in advance of what would be expected in the absence of any treatment (Cardinali et al. 2002). More recently, a retrospective analysis of the data obtained from 134 normal volunteers flying the Buenos Aires - Sydney transpolar route in the past 9 years was published this further supports such a role for exogenous melatonin in resynchronization of sleep cycles (Cardinal et al. 2006). 

Golombek, D. A Cardinali, D. P. (1993). Melatonin accelerates re-entrainment after phase advance of the light-dark cycle in Syrian hamsters. Antagonism by flumazenil. Chronobiol. Int. 10, 435-41. 

Dietary Supplements. In the past 10 years, melatonin, available as a dietary supplement from health food stores or over the Internet, has become a popular sleep agent. Melatonin is a hormone produced by the pineal gland at peak levels during the night. It is believed to help regulate the 24 hour circadian sleep-wake cycle. 

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). 

HT is metabolized by the action of monoamine oxidase by a process of oxidative deamination to yield 5-hydroxyindoleacetic acid (5-HIAA). In the pineal gland, 5-HT is o-methylated to form melatonin. While the physiological importance of this transmitter in the regulation of the oestrus cycle in ferrets would appear to be established, its precise role in man is unknown. Nevertheless, it has been speculated that melatonin plays some... 

In the context of an updated comprehensive evaluation of mood stabilizers, it is worthwhile to mention the recent studies showing a beneficial effect of thyroid hormones and melatonin in rapid-cycling patients. A detailed account of these hormones appears elsewhere in this book series and is briefly described by Halbreich in Chapter 17. 

Melatonin is /V-acetyl-5-methoxytryptamine (Figure 16-2), a simple methoxylated and /V-acetylated product of serotonin found in the pineal gland. It is produced and released primarily at night and has long been suspected of playing a role in diurnal cycles of animals and the sleep-wake behavior of humans. 

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. 

The optimal timing and dose of melatonin have not been established. Current information suggests 5-8 mg of the immediate-release formulation given on the evening of departure and for 1-3 nights after arrival at the new destination. Exposure to daylight at the new time zone is also important to regulate the sleep-wake cycle. 

Serotonin and melatonin are evidently involved in maintenance of the 24-h circadian rhythm of the body (see Section 13).792/792a Melatonin regulates the sexual cycle in photoperiodic animals and influences the onset of puberty.792-794 The serotonin content of the brain is influenced by the diet, being higher after a meal rich in carbohydrates. Serotonin may serve as a chemical message sent from one set of neurons to the rest of the brain, reporting on the nature of dietary intake.784 Melatonin, which can readily form free radicals, may function as part of the body s antioxidant system.795 796... 

The pineal gland appears also to play a role in maintaining the mammalian circadian cycle.1081-1083 The concentration of the pineal hormone melatonin (Fig. 27-11) as well as its precursor N-acetylserotonin and the enzyme serotonin N-acetyltransferase (Eq. 30-4) all fluctuate far more than do the concentrations of other metabolites during the 24-h cycle. These metabolites increase over 10-fold concentration at night and decrease by day. During the daytime the serotonin N-acyltransferase, which forms the precursor, is rapidly... 

Melatonin affects reproduction in seasonally breeding animals. In humans, findings of increased endogenous melatonin in hypogonadism and low concentrations in precocious puberty imply an interaction between melatonin and gonadotropins however, data on the effects of exogenous melatonin are limited (1). In a randomized study in 16 women, melatonin enhanced LH and FSH responses to submaximal GnRH stimuli in the follicular but not the luteal phase of the menstrual cycle (24). 

There was suppression of endogenous melatonin secretion in two of five patients with bipolar disorder after 12 weeks of treatment with high-dose melatonin (10 mg/day) (19). One woman developed an unentrained sleep-wake cycle after melatonin was withdrawn (not previously a feature of her illness), which persisted for several months. 

Leibenluft E, Feldman-Naim S, Turner EH, Wehr TA, Rosenthal NE. Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. J Clin Psychiatry 1997 58(9) 383-8. 

Melatonin N-acetyl-5- methoxytryptamine Manufactured synthetically to mimic the endogenous hormone Sedative-hypnotic regulate sleep-wake cycles used in various other conditions because of antioxidant and immunomodulating effects... 

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 most well-known effect of melatonin is that it regulates the sleep cycle. Production of melatonin by the pineal gland increases with darkness. Increased melatonin levels, in turn, promote sleep. 

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