Melatonin

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Some lower vertebrates (e.g. frogs and lizards) have what is commonly described as a 'third eye': the pineal gland. This is found in the dorsal cranium and is linked to the diencephalon. Despite its trivial name, the pineal gland does not contribute to discriminative vision and its role is merely to detect changes in light intensity so that, in animals with a clear photoperiod, it couples physiological rhythms with the length of the day-light cycle. In mammals, the pineal is not exteriorised but it persists as a brain appendage for the secretion of the hormone, melatonin. (A-acetyl 5-methoxytrypta-mine) which, like 5-hydroxytryptamine (5-HT), is an indole derivative (Fig. 22.2). Melatonin is not a normal metabolite of neuronal 5-HT but it is synthesised from that amine in the pineal gland by the enzyme, 5-hydroxytryptamine A-acetyltransferase. This is a rate-limiting process that shows a circadian rhythm with maximal activity occurring during darkness. The product of this reaction, A-acetyl 5-hydroxytryptamine, is methylated, to form melatonin, by the enzyme hydroxyindole-O-methyltransferase.

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

Figure 22.2 The biosynthetic pathway for melatonin

that connects the SCN with sympathetic innervation of the pineal via the paraventricular nucleus of the hypothalamus.

The effect of noradrenaline on melatonin synthesis appears to be mediated through ^-adrenoceptors, using cyclic AMP as their second messenger, although studies on cultured pinealocytes suggest that this process is potentiated by activation of (^-adrenoceptors (see Hagan and Oakley 1995). However, there is evidence that melatonin synthesis in the pineal is also regulated by dopamine and 5-HT. Finally, some melatonin is synthesised in the retina where the rate-limiting enzyme is tryptophan hydroxylase; this process is rhythmic, even in cultured retinal cells, and it seems to adjust to shifts in the light-dark cycle.

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 (ML1) 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 ML1 agonist such as 2-iodomelatonin, restores the impaired circadian cycle in aged rats.

In humans, poor sleep correlates with low plasma melatonin and can be improved by melatonin administration. This therapeutic approach has been tried especially in individuals whose sleep rhythms are disrupted by shift-work, blindness or 'jet-lag' but its benefits are as yet unconfirmed and, in any case, the mechanisms by which it might reset sleep patterns are unclear. Of course, it must be remembered that other body

Figure 22.3 Possible links in the induction of circadian rhythm between daylight, the suprachiasmatic nucleus and melatonin release from the pineal gland. Some fibres in the optic nerve, projecting from the eye to the lateral geniculate nucleus (LGN) in the thalamus, innervate the suprachiasmatic nucleus (SCN) in the anterior hypothalamus, via the retinohypothalamic tract (RHT). Others project to the SCN from the LGN in the geniculohypothalamic tract (GHT). The release of melatonin into the circulation from the pineal gland (PG) is maximal at night and appears to be controlled partly by noradrenaline released from sympathetic nerves originating in the superior cervical ganglion (SCG). Melatonin receptors are found in the SCN, the removal of which dampens melatonin secretion

Figure 22.3 Possible links in the induction of circadian rhythm between daylight, the suprachiasmatic nucleus and melatonin release from the pineal gland. Some fibres in the optic nerve, projecting from the eye to the lateral geniculate nucleus (LGN) in the thalamus, innervate the suprachiasmatic nucleus (SCN) in the anterior hypothalamus, via the retinohypothalamic tract (RHT). Others project to the SCN from the LGN in the geniculohypothalamic tract (GHT). The release of melatonin into the circulation from the pineal gland (PG) is maximal at night and appears to be controlled partly by noradrenaline released from sympathetic nerves originating in the superior cervical ganglion (SCG). Melatonin receptors are found in the SCN, the removal of which dampens melatonin secretion functions show a circadian rhythm, some of which, such as corticosteroid production (high in morning) and body temperature (low during sleep) could all influence the state of arousal. However, the night-time peak for melatonin secretion normally coincides with the trough for body temperature, and these two events could well be linked. Nevertheless, whether melatonin affects sleep itself, rather than merely the entrainment of the sleep rhythm, is controversial (for a detailed review of this topic see Arendt et al. 1999).

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