The metabolism of indoleamines

Abstract The indoleamine serotonin is involved in many different functions of the central nervous system. There is however no longer a need to precede its hypothesized role as a neurotransmitter agent—with the word “putative” we think that role is totally accepted. The synthesis of 5-HT is now well defined, but less clear is its definitive role in neuropsychiatric disorders. Early work focused on levels of this amine in blood and urine, an approach that although viable and convenient is limited in the inferences they allow regarding the levels of serotonin release in the brain. A recent study using fast-cyclic voltammetry in the human brain while subjects performed a complex stock market game strongly suggests we have missed a key aspect of the phasic release of the transmitter and its potential role in controlling decision making. Where we have previously been searching for metabolic changes of large effect size and perhaps prolonged duration across the life span, pulses of release of millisecond duration may be much more important. The opportunity to widely approach this question is currently out of scope methodologically though. The work of Martin Sarter ’ s lab working with acetylcholine voltammetry has strongly indicated that this might be the case for cholinergic transmission as well, where phasic release seems to play key roles in monitoring the detection of stimulus cues. Clearly in vivo voltammetry in human brain is always going to be a rare opportunity and until somebody defines new noninvasive means of investigating serotonin release over a millisecond timeframe, decisions on the exact role of serotonin in controlling behavior are always going to be subject to questions of temporal specificity. Despite this limitation, our knowledge of serotonin metabolism is now both broad and specific. There is no doubt that compounds inhibiting 5-HT reuptake after its release has benefited millions of people suffering from depression since their introduction in the 1950s. Many specific points of metabolic control from both the melatonin and kynurenine metabolic branches of tryptophan metabolism have yet to be investigated as potential drug targets, notwithstanding the possibilities provided by the existence of multiple serotonin receptor subtypes (see Serotonin receptors nomenclature).