Trace amines are endogenous compounds classically regarded as comprising β-phenylethyalmine, p-tyramine, tryptamine, p-octopamine, and some of their metabolites. They are also abundant in common foodstuffs and can be produced and degraded by the constitutive microbiota. The ability to use trace amines has arisen at least twice during evolution, with distinct receptor families present in invertebrates and vertebrates. The term “trace amine” was coined to reflect the low tissue levels in mammals; however, invertebrates have relatively high levels where they function like mammalian adrenergic systems, involved in “fight-or-flight” responses. Vertebrates express a family of receptors termed trace amine–associated receptors (TAARs). Humans possess six functional isoforms (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9), whereas some fish species express over 100. With the exception of TAAR1, TAARs are expressed in olfactory epithelium neurons, where they detect diverse ethological signals including predators, spoiled food, migratory cues, and pheromones. Outside the olfactory system, TAAR1 is the most thoroughly studied and has both central and peripheral roles. In the brain, TAAR1 acts as a rheostat of dopaminergic, glutamatergic, and serotonergic neurotransmission and has been identified as a novel therapeutic target for schizophrenia, depression, and addiction. In the periphery, TAAR1 regulates nutrient-induced hormone secretion, suggesting its potential as a novel therapeutic target for diabetes and obesity. TAAR1 may also regulate immune responses by regulating leukocyte differentiation and activation. This article provides a comprehensive review of the current state of knowledge of the evolution, physiologic functions, pharmacology, molecular mechanisms, and therapeutic potential of trace amines and their receptors in vertebrates and invertebrates.

The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.

Mining of the human genome has revealed approximately 7000 novel proteins, which could serve as potential targets for the development of novel therapeutics. Of these, approximately 2000 are predicted to be G-protein coupled receptors. Within this group of proteins, a family of 18 mammalian receptors has recently been identified that appear to exhibit selectivity toward the so-called trace amines. The trace amines are a family of endogenous compounds with strong structural similarity to classical monoamine neurotransmitters, consisting primarily of 2-phenylethylamine, m- and ptyramine, tryptamine, m- and p-octopamine and the synephrines. The endogenous levels of these compounds are at least two orders of magnitude below those of neurotransmitters such as dopamine, noradrenaline and 5-HT. The effects of these low physiological concentrations have been difficult to demonstrate but it has been suggested that they may serve to maintain the neuronal activity of monoamine neurotransmitters within defined physiological limits. Such an effect of trace amines would make them ideal candidates for the development of novel therapeutics for a wide range of human disorders. Although the demonstration of a trace amine family of receptors has seen a resurgence of interest in these endogenous compounds, with recent articles reviewing trace amine pharmacological and physiological responses, the potential clinical utility of the trace amine receptors has not been specifically addressed. Historically, trace amines have been implicated in a diverse array of human pathologies ranging from schizophrenia to affective disorders to migraine. Recent studies have strengthened some of this historical data by linking trace amine receptor polymorphisms and mutations to distinct clinical conditions. The aim of the current article is to review the previous studies linking trace amines to human pathology in the context of the recently discovered trace amine receptors and evidence of the existence of trace amine receptor polymorphisms and mutations associated with such disorders. In addition, recent evidence linking trace amines to the development of drug dependence will be discussed.