Serotonin modulates the synthesis of melatonin as an autocrine neurotransmitter in the pineal gland



The pineal gland secretes melatonin at night mainly under the effect of sympathetic adrenergic inputs. Many other neurotransmitters are found in the pineal gland, suggesting a potential fine modulation of melatonin release. Serotonin as a precursor of melatonin synthesis is known to be released significantly from pinealocytes and its receptor is also expressed in pinealocytes. By identifying the release mechanism, cell signaling in pinealocytes and its effect on norepinephrine-induced melatonin secretion, our study defines serotonin as an autocrine neurotransmitter in the pineal gland and suggests possible modulatory targets for melatonin secretion. .


The pineal gland secretes melatonin mainly at night. Regulated by norepinephrine released from sympathetic nerve endings, pinealocyte adrenergic receptors activate aralkylamine NOT-acetyltransferase which converts 5-hydroxytryptamine (5-HT, serotonin) into NOT-acetylsérotonin, precursor of melatonin. Previous studies by our group and others reveal significant constitutive secretion of 5-HT by pinealocytes. Here, using mass spectrometry, we demonstrated that 5-HT is secreted primarily via a decynium-22 sensitive plasma membrane equilibrating monoamine transporter instead of the typical exocytotic quantum secretion. Activation of endogenous 5-HT receptors on pinealocytes evoked intracellular Ca2+ rise blocked by RS-102221, a 5-HT antagonist2C receivers. The 5-HT applied did not induce melatonin secretion by itself, but potentiated the melatonin secretion caused by submaximal norepinephrine. Additionally, RS-102221 reduced norepinephrine-induced melatonin secretion in pineal gland bands, even when no exogenous 5-HT was added, suggesting that 5-HT which is constitutively released by Pinealocytes accumulate sufficiently in the tissue to act as an autocrine feedback signal sensitizing the release of melatonin.


    • Accepted September 15, 2021.
  • Author contributions: research designed by BHL, BH and D.-SK; BHL and D.-SK carried out research; BHL and D.-SK analyzed the data; and BHL, BH and D.-SK wrote the article.

  • The authors declare no competing interests.

  • Editors: JB, University of Michigan, Ann Arbor; EMM, National University of Cuyo Mendoza.

  • This article contains additional information online at


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