Circadian rhythms. See

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. 

Multiple regulation, see Model based on two instability mechanisms Multiple time scales effect on birhythmicity, 108 effect on bursting, 146 effect on oscillations, 66-8,73 see also Quasi-steady-state hypothesis Muscle, glycolytic oscillations, 37,344 Mutants of circadian rhythm, see frq gene per gene tim... 

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). 

Circadian Rhythms. Figure 1 Mammalian circadian system is organized as a hierarchy of multiple clocks thatfunction to synchronize timing of internal processes between each other and with the environment. See details in the text. 

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). 

The first example shows the circadian rhythm of the cortisol level. As an activator of gluconeogenesis (see p. 158), cortisol is mainly released in the early morning, when the liver s glycogen stores are declining. During the day, the plasma cortisol level declines. 

Some prominent 3-substituted derivatives include skatole (3-methylin-dole), which has a faecal odour, and indoIyl-3-acetic acid (sold as a plant rooting powder). Many indoles are biologically important for example, tryptamine is the precursor of two hormones serotonin, a vasoconstrictor, and melatonin, which is involved in the control of circadian rhythm. In addition, the amino acid tryptophan is an essential component of proteins (see Box 7.1). 

One of the most consistent findings is the sleep disturbance that often precedes and may even trigger a manic phase ( 46). Studies on circadian rhythms have demonstrated that many aspects of the sleep cycle are phase-advanced in mania (i.e., occur earlier than normal), and often these patterns resemble the free-running rhythms seen in normal individuals who are removed from all time cues. In addition, there is a blunting of amplitude and a doubling of the sleep-wake cycle up to 48 hours. Lithium is known to delay the sleep-wake cycle and often slow such free-running rhythms, which in turn are partly modulated by neurotransmitters such as NE, 5-HT, and acetylcholine. Further, manipulation of the sleep-wake cycle may prevent a manic episode or be used to treat the depressive phase (e.g., sleep deprivation therapy see also the section Experiments in Chapter 8). 

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. 

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... 

Pro-inflammatory cytokines (see p. 432 et seq.) can also induce sleep, the effect depending on the concentration of the cytokine and the time of day. The effect on the sleep profile (increased non-REM and decreased REM sleep) appears to depend on the increased synthesis of prostaglandin D2 and nitric oxide which then alter the circadian rhythm. It is also known that some pro-inflammatory cytokines can affect the reuptake of 5-HT which plays an important role in regulating the sleep-wake profile. The endogenous fatty acid, oleamide, can cause sedation and induce sleep by activating cannabinoid receptors but also by potentiating the action of benzodiazepines on their receptor sites. Whether such action is of physiological relevance is presently unknown. 

To determine the effect of circadian rhythms on anticancer drug administration, it is important to incorporate the link between the circadian clock and the cell cycle. Entrainment by the circadian clock can be included in the automaton model by considering that the protein Weel undergoes circadian variation, because the circadian clock proteins CLOCK and BMAL1 induce the expression of the Weel gene (see Fig. 10.1b) [3-5]. Weel is a kinase that phosphorylates and thereby inactivates the protein kinase cdc2 (also known as the cyclin-dependent kinase Cdkl) that controls the transition G2/M and, consequently, the onset of mitosis. 

The time of falling asleep is determined by three factors, which in normal sleepers occur at bedtime. These are (a) circadian rhythm, i.e. the body s natural clock in the hypothalamus triggers the rest/ sleep part of the sleep-wake cycle, (b) tiredness, i.e. time since last sleep, usually about 16 hours and (c) lowered mental and physical arousal. If one of these processes is disrupted then sleep initiation is difficult, and it is these three factors that are addressed by a standard sleep hygiene program (see below). Early in the course of insomnia rigorous adherence to sleep hygiene principles alone may restore the premorbid sleep pattern but in some patients the circadian process is less stable and they are less susceptible to these measures. 

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