Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Extrapineal melatonin: sources, regulation, and potential functions.

Thyroid hormones states and brain development interactions

Threads of evidence from recent experimentation in retinal morphology, neurochemistry, electrophysiology, and visual perception point toward rhythmic ocular processes that may be integral components of circadian entrainment in mammals. Components of retinal cell biology (rod outer-segment disk shedding, inner-segment degradation, melatonin and dopamine synthesis, electrophysiological responses) show self-sustaining circadian oscillations whose phase can be controlled by light-dark cycles. A complete phase response curve in visual sensitivity can be generated from light-pulse-induced phase shifting. Following lesions of the suprachiasmatic nuclei, circadian rhythms of visual detectability and rod outer-segment disk shedding persist, even though behavioral activity becomes arrhythmic. We discuss the converging evidence for an ocular circadian timing system in terms of interactions between rhythmic retinal processes and the central suprachiasmatic pacemaker, and propose that retinal phase shifts to light provide a critical input signal.

The visual input stage of the mammalian circadian pacemaking system: I. Is there a clock in the mammalian eye?

Dr. Walls has written a comprehensive treatise on the vertebrate eye in which he includes and correlates an immense amount of data on the anatomy and physiology of the eye in relation to the various environments in which it functions. The 689 pages of text are very readable, appealing to the interests of the biologist, clinician or lay reader, and constitute, therefore, as the author intended, rather a textbook on the eye than merely a reference source. There are three major divisions of the text. The first, entitled "Basic," consists of a discussion of the anatomy and histology of the human eye and orbit. Adequate material on the structure of the retina is followed by a clear and welcome discussion of the theories of the visual processes, including color vision. In addition there is a brief resume of the development of the eye. The second division concerns itself with ocular

The Vertebrate Eye and Its Adaptive Radiation.

We studied the effect of orally administered melatonin on intraocular pressure in humans We suppressed serum melatonin levels by exposing our subjects to bright light Our experiments suggest that melatonin lowers intraocular pressure in man This may prove to be a therapeutically useful agent since melatonin appears to be relatively free of side effects and is effective in small quantities

Effect of melatonin on intraocular pressure

Melatonin's effects were studied in male golden hamsters (Mesocricetus auratus) distributed among five surgical groups (nonoperated, sham-pinealectomized, sham-pinealectomized plus black plastic shielding of the pineal region, pinealectomized, and pinealectomized plus black plastic shielding of the pineal region) and three injection groups (vehicle only, 25 micrograms melatonin, and 2,500 micrograms melatonin). Injections (s.c.) were daily for 28 d at L11 to L11.75 in a (light:dark) L:D 14:10 artificial photoperiod. Animals (N = 112) were killed and dissected on the day after the last injection (at 55-65 d of age). None of the surgical procedures affected weights of eyes or their parts, nor did they influence the effects of administered melatonin on the eyes. Melatonin caused an increase in absolute and relative eye weight and an increase in fluid content of intraocular space. The magnitudes of these effects were positively related to melatonin dose. These same eyes had a progressively lower weight of nonlenticular tissues with low to high doses of melatonin, probably in relation to greater fluid content, and suspected increase in intraocular pressure. Lens wet and dry weights were significantly greater in animals receiving melatonin, but only at the high dose. These actions of melatonin are likely to be direct and are shown to not require the presence of the pineal. Experiments of other designs are suggested in order to determine whether the effects of the low, near physiological, dose of melatonin represent physiological actions of endogenous melatonin, synthesized and released within the eye. However, effects of large doses of melatonin on the eye are still noteworthy in relation to interpretation of experiments employing such dosages, and of disease states involving changes in intraocular pressure.

Increases in volume, fluid content, and lens weight of eyes following systemic administration of melatonin.

This study aimed to determine the extraretinal effects of melatonin upon the eyes of an avian species, the House Finch (Carpodacus mexicanus). Twelve birds (full-grown, second-year males) each received a Silastic tubing intraperitoneal implant, six containing melatonin (average release = 24 micrograms/d/bird; = M birds) and six being empty (= C birds). Microscopic study of pupillary and palpebral behaviors during the final week demonstrated lesser pupillary diameters and interpalpebral distances in M birds under all test conditions. These effects could have diminished mean light levels reaching parts of the retina. Characteristics of the relative miosis and ptosis of M birds resemble signs in some CNS disorders, such as altered inhibition of the Edinger-Westphal nucleus, and especially lesions in, or lowered activity of, higher sympathetic centers (a subtype of Horner's syndrome). Weights of eyes and their parts were the same in M and C birds, contrasting with previously reported results from male Golden Hamsters, possibly due to species differences and/or preexperimental attainment of full growth in the finches. Effects of melatonin on pupillary and palpebral behaviors, demonstrated here for the first time, foster caveats for simplistic experimental designs and interpretations with melatonin when sensory-neural-behavioral interactions are affected. Quantitative changes in pupillary and palpebral behaviors may, nevertheless, provide a window for monitoring central actions of melatonin in living test subjects in chronic studies.

Effects of Melatonin Implants on Structures and Behaviors of the House Finch (Carpodacus mexicanus) Eye

Glycogen level in and size of pinealocytes of the feral, white-footed mouse Peromyscus leucopus, were studied by a semiquantitative histochemical method to determine whether seasonal changes exist in them under natural conditions, what temporal pattern they exhibit, and whether 24-hour changes in these parameters exist in different seasons, as shown in the laboratory dd-mice. Marked seasonal changes were seen in both glycogen levels and nuclear densities (ANOVA p less than 0.005). The size of pinealocytes at 09:00 to 10:00 showed one peak (and nadir) seasonal change, with the smallest size in winter (December and February) and a larger size in warmer seasons, with the maximum value in July. Glycogen level in pinealocytes at 09:00 to 10:00 showed bimodal seasonal changes, with lower levels in fall and spring and higher levels in winter and summer. In fall, a circadian trend in glycogen level in pinealocytes was seen, with a higher level at the end of the light period. In winter, the glycogen levels were very high at 09:00, 13:00, 17:00, and 21:00 examined and showed dampening of time-of-day differences. On the other hand, the size of pinealocytes followed a time-of-day change (P less than 0.005), being largest at 13:00 and smallest at 21:00. Thus, marked changes in quantitative structure and chemical activities, suggesting changes in functional activity, in pinealocytes were noted especially in severe, cold winter.

Seasonal Changes in Glycogen Level and Size of Pinealocytes of the White‐Footed Mouse, Peromyscus leucopus: A Semiquantitative Histochemical Study

Effects of thyroid hormone on light/dark melatonin synthesis and release by young and maturing rat pineal glands in vitro.

Pineal weight and serotonin (5-HT) and norepinephrine (NE) contents were studied in male Sprague-Dawley rats that were maintained under controlled light:dark conditions (LD 14:10; lights on 0700-2100) and that received daily subcutaneous injections of either melatonin (20 micrograms in 0.1 ml per animal) or the same volume (0.1 ml) of vehicle alone, at one of two times (0800-0900 or 1800-1900). Animals were sacrificied at four times (1000, 1400, 2000, or 2300) on the day after the last of the 7 consecutive d of injection. Pineal glands were quickly weighed and then frozen for 5-HT and NE assay by the Maickel and Miller extraction and fluorescence methods. Pineal NE content showed differences related to time of day, in confirmation of early work. But no effects attributable specifically to melatonin were found. Melatonin also failed to affect pineal 5-HT content significantly. But injection of either melatonin or vehicle at 1800-1900 led to a reduction in 5-HT content averaging 36% when sampled at either 2000 or 2300, and in comparison with animals injected at 0800-0900. It is suggested that a stresslike or zeitgeberlike effect of injections within a critical period at the end of the daily light phase can cause an earlier-than-normal daily fall in pineal 5-HT content.

Effects of Melatonin and Control Injections on Pineal Serotonin and Norepinephrine: Afternoon Injections Lower Serotonin Levels Thirty‐Six Percent at Light‐Dark Transition

W.B. Quay

Papers

Increases in volume, fluid content, and lens weight of eyes following systemic administration of melatonin.

Effects of Melatonin Implants on Structures and Behaviors of the House Finch (Carpodacus mexicanus) Eye

Seasonal Changes in Glycogen Level and Size of Pinealocytes of the White‐Footed Mouse, Peromyscus leucopus: A Semiquantitative Histochemical Study

Effects of thyroid hormone on light/dark melatonin synthesis and release by young and maturing rat pineal glands in vitro.

Effects of Melatonin and Control Injections on Pineal Serotonin and Norepinephrine: Afternoon Injections Lower Serotonin Levels Thirty‐Six Percent at Light‐Dark Transition