Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems. Trace amines play significant roles in regulating the quantity of monoamine neurotransmitters in the synaptic cleft of monoamine neurons with co-localized TAAR1. They have well-characterized presynaptic amphetamine-like effects on these monoamine neurons via TAAR1 activation; specifically, by activating TAAR1 in neurons they promote the release and prevent reuptake of monoamine neurotransmitters from the synaptic cleft as well as inhibit neuronal firing. Phenethylamine and amphetamine possess analogous pharmacodynamics in human dopamine neurons, as both compounds induce efflux from vesicular monoamine transporter 2 (VMAT2) and activate TAAR1 with comparable efficacy. Like dopamine, norepinephrine, and serotonin, the trace amines have been implicated in a vast array of human disorders of affect and cognition, such as ADHD,<ref name="Neuropsychopharm"> depression and schizophrenia, among others. <ref name="Review 2009"> Trace aminergic hypo-function is particularly relevant to ADHD, since urinary and plasma phenethylamine concentrations are significantly lower in individuals with ADHD relative to controls and the two most commonly prescribed drugs for ADHD, amphetamine and methylphenidate, increase phenethylamine biosynthesis in treatment-responsive individuals with ADHD. A systematic review of ADHD biomarkers also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.

List of trace amines

The human trace amines include: While not trace amines themselves, the classical monoamines norepinephrine, serotonin, and histamine are all partial agonists at the human TAAR1 receptor; dopamine is a high-affinity agonist at human TAAR1. N-Methyltryptamine and N,N-dimethyltryptamine are endogenous amines in humans, however, their human TAAR1 binding has not been determined

Concentrations

Trace amines are so-named because they are present in the nervous system at trace or very concentrations. These concentrations are much lower than for classical monoamine neurotransmitters like serotonin, dopamine, and norepinephrine. However, the rapid metabolic turnover of trace amines, consequent to strong susceptibility to monoamine oxidases, is suggestive that they may be present as chemical synapses at much higher concentrations than predicted by steady-state measures.

History

A thorough review of trace amine-associated receptors that discusses the historical evolution of this research particularly well is that of Grandy.