N-Acetylserotonin

N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. It is produced from serotonin by the enzyme aralkylamine N-acetyltransferase (AANAT) and is converted to melatonin by acetylserotonin O-methyltransferase (ASMT). Like melatonin, NAS is an agonist at the melatonin receptors MT1, MT2, and MT3, and may be considered to be a neurotransmitter. In addition, NAS is distributed in some areas of the brain where serotonin and melatonin are not, suggesting that it may have unique central duties of its own instead of merely functioning as a precursor in the synthesis of melatonin.

Recently, NAS has been shown to act as a potent TrkB receptor agonist, while serotonin and melatonin are not. It produces robust antidepressant, neuroprotective, and neurotrophic effects that are TrkB-mediated. In addition, AANAT knockout mice which lack NAS display significantly greater immobility times versus control mice in assays of depression like the forced swim test.

NAS may also play a major role in the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). The SSRI fluoxetine and the MAO-A inhibitor clorgyline upregulate AANAT indirectly through serotonergic mechanisms and thereby increase NAS levels after chronic administration, and this correlates with the onset of their antidepressant effects. Furthermore, light exposure inhibits the synthesis of NAS and reduces the antidepressant effects of MAOIs. These data strongly support a role for NAS in mood regulation and in antidepressant-induced therapeutic benefits.

Through a currently unidentified mechanism, NAS may be the cause of the orthostatic hypotension seen with clinical treatment of MAOIs. It reduces blood pressure in rodents, and pinealectomy (the pineal gland being a major site of NAS and melatonin synthesis) abolishes the hypotensive effects of clorgyline. Why orthostatic hypotension is commonly seen with MAOIs but not SSRIs (both of which increase NAS levels) however, is unknown.