Mechanisms of circadian serotonin synthesis and release

Serotonin (5-hydroxytryptamine; 5-HT) synthesis and release are thought to be high during the day and low at night in the pineal. We identify a sharp rise in 5-HT synthesis and release soon after the lights are off during the dark phase of the circadian cycle, which precedes the nocturnal rise in melatonin synthesis and secretion. This tri-phasic 5-HT release, which consists of constant levels during the day, elevated levels at early night, a low level at late night, persists in the constant darkness, and is influenced strongly by light at night. The early nocturnal peak of 5-HT secretion is controlled directly by the sympathetic innervation originating from the superior cervical ganglion. We find that the marked decrease of 5-HT contents and release later at night is solely due to the consumption by melatonin synthesis and that the early nocturnal increase of 5-HT synthesis and release is independent of the melatonin synthesis. In the absence of melatonin synthesis, the tri-phasic 5-HT release becomes bi-phasic, with the nighttime level twice as high as that of the day value. We further demonstrate that the early night increase in 5-HT synthesis is controlled by beta-adrenergic receptor, and that the increased 5-HT release is mediated by alpha-adrenergic signaling. These observations suggest that 5-HT synthesis and secretion in the pineal is diurnally regulated independently of melatonin formation by adrenergic innervation, which may serve as a unique model system for investigating the regulation of 5-HT synthesis and release.