Physiological control of melatonin synthesis and secretion: mechanisms, generating rhythms in melatonin, methoxytryptophol, and arginine vasotocin levels and effects on the pineal of endogenous catecholamines, the estrous cycle, and environmental lighting.

Daily rhythms in pineal methoxyindole metabolism have been described in rodents and humans: serotonin levels in rat pineals are highest during the daylight hours and fall markedly soon after the onset of darkness, coincident with increases in the levels of pineal melatonin and 5-methoxy-tryptophol and the activities of pineal serotonin-N--acetyltransferase (SNAT) and hydroxyindole-O-methyltransferase (HIOMT). The fact that the levels of melatonin and 5-methoxytryptophol vary in parallel suggests that the major factor generating the methoxyindole rhythms is not SNAT activity, as has been suggested, but a proximal step, perhaps a change in the availability (for metabolism) of "stored" serotonin. Melatonin levels in human serum and urine exhibit rhythms similar to those observed in rats, i.e., they rise sharply during the daily dark period. When the onset of darkness is delayed by 12 hours, human melatonin rhythms usually require 3 or 4 days to adjust to the new lighting regimen. Environmental factors, other than light, that activate the sympathetic nervous system or cause epinephrine to be secreted from the adrenal medulla (e.g., the stress of immobilization; insulin-induced hypoglycemia) can override the inhibitory effects of light and accelerate melatonin synthesis. Melatonin levels in rat blood and urine are lowest during the proestrous and estrous phases of the estrous cycle. Although this effect of the ovarian steroid hormones is accompanied by a reduction in urinary norepinephrine levels, it is not caused simply by a decrease in the quantity of norepinephrine acting on the pineal but also involves a direct action of the hormones. Ovariectomy increases serum melatonin levels, whereas the administration of estradiol plus progesterone (to ovariectomized animals) lowers melatonin levels. The spectral and intensity-response characteristics of the photic inhibition of melatonin synthesis have been established for the rat. Rhythms in melatonin synthesis apparently persist among animals placed in environments of continuous darkness; the source of the cyclic signal (mediated by the pineal sympathetic nerves) has not yet been identified. Preliminary evidence suggests that levels of a peptide hormone, arginine vasotocin, in rat pineals and sera also exhibit daily rhythms and are increased by norepinephrine.