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The various aspects of the existing knowledge on the physiological role of melatonin and its mode of action in circadian rhythms and sleep are presented. Furthermore, the possibility of its clinical application in maintenance of sleep under regular and environmental changes is discussed.

Dopamine metabolism was studied in dystrophic retinal degeneration slow (rds) mice which carry a mutation in the rds/peripherin gene. RDS mutations in humans cause several forms of retinal degeneration. Dopamine synthesis and utilization were analyzed at various time points in the diurnal cycle in homozygous rds/rds retinas which lack photoreceptor outer segments and heterozygous rds/+ retinas which have short malformed outer segments. Homozygous retinas exhibited depressed dopamine synthesis and utilization while the heterozygous retina retained a considerable level of activity which was, nevertheless, significantly lower than that of normal retinas. By one year, heterozygous rds/+ retinas which had lost half of the photoreceptors still maintained significant levels of dopamine metabolism. Normal characteristics of dopamine metabolism such as a spike in dopamine utilization at light onset were observed in mutant retinas. However, light intensity-dependent changes in dopamine utilization were observed in normal but not rds/+ retinas. The findings of this study suggest that human patients with peripherin/rds mutations, or other mutations that result in abnormal outer segments that can still capture light, might maintain light-evoked dopamine metabolism and dopamine-dependent retinal functions during the progression of the disease, proportional to remaining levels of light capture capabilities. However, visual deficits due to reduced light-evoked dopamine metabolism and abnormal patterns of dopamine utilization could be expected in such diseased retinas.

Dopamine is an important retinal neurotransmitter and neuromodulator that regulates key diurnal cellular and physiological functions. In the present study we carried out a comprehensive analysis of dopamine metabolism during the light phase of the diurnal cycle and evaluated the presence of diurnal and circadian rhythms of dopaminergic activity in the mouse retina. Steady-state levels of dopamine did not change significantly between the dark phase (night) and the light phase (day) of the diurnal cycle, nor did they change between early and late points in the day. Dopamine synthesis and utilization, however, revealed significant alterations between the night and day and between early and late time points in the day. A spike in synthesis and utilization was measured immediately after light onset at the end of the night. Subsequently, dopamine synthesis and utilization partially declined and remained stable throughout the remainder of the day at a level that was significantly higher than that at night. The burst of dopamine synthesis and utilization at the beginning of the day is entirely light evoked and not driven by a circadian clock. Similarly, there was no circadian rhythm in dopamine synthesis and utilization in mice kept in constant darkness. This daily pattern of dopaminergic activity may impact upon a variety of temporally regulated retinal events. Moreover, these data will provide a basis for evaluating the role of dopamine in retinal pathology in mouse models of retinal degeneration where mutations affect light perception.

An abnormal circadian pattern of melatonin was found in a group of young adults with an extreme autism syndrome. Although not out of phase, the serum melatonin levels differed from normal in amplitude and mesor. Marginal changes in diurnal rhythms of serum TSH and possibly prolactin were also recorded. Subjects with seizures tended to have an abnormal pattern of melatonin correlated with EEG changes. In others, a parallel was evidenced between thyroid function and impairment in verbal communication. There appears to be a tendency for various types of neuroendocrinological abnormalities in autistics, and melatonin, as well as possibly TSH and perhaps prolactin, could serve as biochemical variables of the biological parameters of the disease.

The diurnal levels of c-fos mRNA were studied in the mouse retinas by means of RNA blot analysis. Mice were kept on a 12/12 h dark/light cycle and gene expression was studied at various time points during the day and night periods. The highest levels of c-fos mRNA were measured during the first half of the night period. The high levels persisted for about 4-5 h. The c-fos mRNA levels declined during the second half of the night period and remained low during the day period. Continuous illumination of mice during the first hours of the night period prevented the increase in c-fos mRNA. If mice were kept in the dark during the day period, they failed to show an increase in c-fos mRNA levels in the subsequent night period. Hence, following activation of c-fos during the night period, a refractory period exists at which illumination is required before c-fos can be induced again by dark. Although light appears to suppress the activation of c-fos in the night period, a short lived burst in c-fos expression of 30-60 min in duration was observed when dark-adapted animals were illuminated, either at the transition between the dark and light period or during the dark period. Thus, it appears that c-fos is activated in at least two different cell types in the retina which respond differently to light and dark stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Sham-operated and pinealectomized male rats were maintained at 14 h light:10 h dark cycles (lights-on 5.00 h) and injected daily, for 14 days, with oxazepam or vehicle. 125I-melatonin binding was recorded in synaptosomes prepared at 10.00, 18.00, and 24.00 h from the hypothalamus, hippocampus and medulla-pons of the rats. In the sham-operated, vehicle treated rats, specific 125I-melatonin binding in all brain areas studied was higher at 18.00 h, whereas in the oxazepam-treated animals, binding was higher at 24.00 h than at the other times tested. In the pinealectomized, vehicle-treated rats, the binding recorded at 18.00 h in all three brain areas, was lower than at the other times of day tested. Oxazepam treatment decreased 125I-melatonin binding at 24.00 h in the hippocampus and medulla-pons of the pinealectomized rats and did not significantly affect the binding in the hypothalamus. These results indicate the ability of oxazepam, pinealectomy and their combination, to manipulate the diurnal variations in 125I-melatonin binding sites in the rat brain.

Conflicting results on changes of the diurnal melatonin rhythms of patients with affective disorders have been reported in the literature. The heterogeneous data may derive from the great discrepancy in the diagnostic criteria of different authors. A study of 12 schizoaffective and chronic schizophrenic psychotic patients found a constant pattern of an obliterated nocturnal melatonin rise only in the latter group. The presence or absence of the nocturnal melatonin rise was determined in drug-free hospitalized patients and remained unchanged despite 2 months of drug treatment including large doses of neuroleptics. This finding, when confirmed in a larger number of patients, could possibly serve as a marker for the type of mental disorder, drug to be applied and response expected.

Direct (via the skull) and indirect (via the eyes) light on the rate of adaptation of circadian rhythms of pineal, retina and serum indoleamines and of locomotor activity was examined by observing photoperiod reversal in eye covered and normally sighted chickens. Eye covering did not affect indoleamine levels nor locomotor activity on the regular light:dark (L:D) cycle. However, following photoperiod reversal, the eye covered chickens showed slower rates of adaptation of retinal melatonin and locomotor activity to the new L:D cycle than did the normal sighted chickens. Pineal and serum indole levels were unaffected by eye covering. Our results in birds indicate that 1) light to the eye has a role in governing retinal melatonin and locomotor activity, 2) the pineal is directly photosensitive, and 3) the endogenous rhythm of pineal melatonin may play a role in the entrainment of the locomotor rhythm in the chicken.

The binding of 125I-melatonin to synaptosomes prepared from whole brains of male rats of the CD strain and from the brain, hypothalamus and striatum of male rats of the Sabra-Wistar strain was assessed throughout a 24 h period. The animals were maintained under a daily schedule of 14 h light (05:00-19:00 h) and 10 h darkness. In whole brain preparations the density of binding sites at 18:00 h was higher by about 70% than at 02:00 h with no variations in apparent affinity of the binding sites throughout the daily period. Specific binding of 125I-melatonin was found in both hypothalamus and striatum of the male rat with a distinct diurnal variation in binding site density in the hypothalamus only. The density of 125I-melatonin-binding sites in the hypothalamus was maximal between 10:00 and 18:00 h and dropped sharply after the lights went off. The apparent 125I-melatonin-binding affinities in these regions were constant and very similar to those in whole brain preparations. The daily variations in densities of 125I-melatonin-binding sites in discrete brain areas may represent a diurnal rhythmicity in the responsiveness of the neuroendocrine axis to melatonin.

The distribution of 125I-melatonin binding sites in the male Syrian hamster brain was recorded at 3 times over a 24 h period. The binding in the hypothalamus, hippocampus, medulla-pons and midbrain of the hamsters varied significantly over the 24 h period with different patterns and phases. No such variations were observed in the parietal cortex. Daily morning (10.00 h) or late afternoon (18.00 h) injections of melatonin for 28 days markedly increased the serum concentrations of melatonin at all times recorded. Serum concentrations of testosterone were significantly lower in animals injected with melatonin in the late afternoon than in the untreated controls; no such decrease was observed in animals injected in the morning despite the continuously elevated levels of circulating melatonin. The daily melatonin injections did not significantly affect 125I-melatonin binding in the hypothalamus, parietal cortex and medulla-pons. In the midbrain, 125I-melatonin binding decreased regardless of the time of injection. In the hippocampus, morning melatonin injections caused a marked decrease in 125I-melatonin binding at all times recorded whereas melatonin injected in the late afternoon led to a decrease in 125I-melatonin binding at 10.00 h only. These results indicate diurnal variations in 125I-melatonin binding sites in discrete brain areas of the golden hamster, persisting despite prolonged duration of elevated levels of circulating melatonin. The differential effects of timed melatonin injections on the hippocampal 125I-melatonin binding sites are positively correlated with the counter-antigonadal response produced by morning melatonin injections.