Sympathetic denervation of the pineal in mammals abolishes the rhythmic synthesis of melatonin and the light-dark control of its production. Norepinephrine is clearly the major transmitter, acting via beta-1-adrenoceptors with potentiation by alpha-1 stimulation, but the role of neural serotonin is probably not negligible. There is a day-night variation in pineal norepinephrine, with highest values at night, approximately 180 degrees out of phase with the pineal serotonin rhythm. cAMP acts as a second messenger and stimulates AA-NAT activity. Beta-adrenergic receptor binding sites in the rat pineal vary over a 24-hour period, the lowest number being found toward the end of the dark phase, increasing shortly after lights on (12). There is evidence for modulation of melatonin synthesis in vitro by other factors, notably neuropeptides (14), but their physiological importance remains obscure. Table 1 summarises factors influencing melatonin secretion and production.

Melatonin is synthesized and secreted during the dark phase of the day in virtually all species (12). In most vertebrates the rhythm is endogenous, that is, internally generated. It persists in the absence of time cues, in general assuming a period deviating slightly from 24 hours, and is thus a true circadian rhythm(16, 17). Lesions of the SCN lead to a loss of the vast majority of circadian rhythms including melatonin (18). Circadian rhythms are entrained (synchronized) to the 24-hour day primarily by light-dark cycles. Factors (zeitgebers) other than light-dark cycles which are involved in entrainment include behavioral imposition such as forced activity and rest, social and nutritional (rhythmic feeding) cues, temperature variations, knowledge of clock time, certain drugs, possibly electromagnetic fields and melatonin itself (19).

Melatonin secretion is related to the length of the night: The longer the night, the longer the duration of secretion in most species (12). Ocular (not extra-ocular) light serves to entrain/synchronise the rhythm to 24h and to suppress secretion at the beginning and/or the end of the dark phase (Fig 2). The amount of light required to suppress melatonin secretion during the night varies from species to species, with time of night, and with previous light exposure (20-22). In humans, 2500 lux full spectrum light (domestic light is around 100 to 500 lux) is required to completely suppress melatonin at night (22). However much lower intensities will partially suppress and shift the rhythm in humans (23, 24). Image forming vision (rods and cones) is not required for suppression of melatonin, or indeed for synchronising /phase shifting the circadian clock. A novel non-image forming photoreceptor system is implicated, with evidence for a pivotal role of a new opsin: melanopsin (25). In humans maximum suppression for equal numbers of photons is given by blue light (459-465nm) with an action spectrum that is distinct from that of scotopic and photopic vision (26, 27).

Figure 2. Diagrammatic representation of the control of production and the functions of melatonin, with regard to seasonal and circadian timing mechanisms. RHT- retino-hypothalamic tract, NA – norepinephrine (noradrenalin), SCN - suprachiasmatic nucleus, PVN - paraventricular nucleus, SCG - superior cervical ganglion. The melatonin rhythm is generated by a closed loop negative feedback of clock gene expression in the SCN, Clock and Bmal, positive stimulatory elements, Per, Cry, negative elements, CCG, clock controlled genes. The SCN via neural pathways drives the pineal melatonin rhythm. Per and NAT mRNA oscillate in the pineal although post transcription control is evident in some species. Melatonin influences SCN activity via one or more receptors. Melatonin conveys photoperiodic information influencing the pattern of per expression in the pars tuberalis for the control of seasonal prolactin variations. Melatonin target sites in the hypothalamus influencing seasonal variations in reproductive hormones have yet to be fully defined. Based on an original diagram by Dr Elisabeth Maywood, MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Road Cambridge, CB2 2QH, UK.

The initial treatment for winter depression (SAD) with bright light was based on the assumption that melatonin duration was a seasonal signal in humans (28). In order to demonstrate daylength dependence of melatonin secretion in humans it has been necessary to maintain subjects in total darkness for 14h per day for 2 months, when the secretion profile is clearly longer than after 10h total darkness for two months, with accompanying changes in body temperature and sleep (29). This photoperiodic response has sometimes been observed in polar regions and even in subjects living according to the natural light dark cycle in temperate regions. The most consistent seasonal observation in humans is that melatonin profiles show a phase change from winter to summer, with earlier secretion in summer than in winter (30).

A single daily light pulse of suitable intensity and duration in otherwise constant darkness is sufficient to phase shift and to synchronize the melatonin rhythm to 24 hours in animals (31). Phase shifting and entrainment (synchronisation with an appropriate phase) have been demonstrated in humans with suitable intensity, spectral composition and duration of light treatment (32-34). However, the relative contribution of light in a normal environment with other time cues remains to be fully determined. Studies in Antarctica suggest that a structured social routine in a dim light environment suffices to synchronize melatonin to 24 hours in most people (12). However, many blind people with no conscious or unconscious light perception living in a normal social environment show 'free running' or abnormally synchronised melatonin and other circadian rhythms (35-37). Moreover the incidence of circadian desynchrony, with its attendant sleep and other problems, is directly related to the degree of light perception of the individual. The less light the more likely is desynchrony to occur, and subjects with no eyes have all shown this phenomenon to date .