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 Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. Although they can be synthesized within parent monoamine

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

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 Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...

of monoamine neurons with 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 Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

possess analogous

pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

in human dopamine neurons, as both compounds induce efflux from vesicular monoamine transporter 2 (VMAT2) and activate TAAR1 with comparable efficacy. Like

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, and

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

, the trace amines have been implicated in a vast array of human disorders of affect and cognition, such as ADHD, depression, and

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

, among others. 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 Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

, increase phenethylamine biosynthesis in treatment-responsive individuals with ADHD. A

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

of ADHD

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

s also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.

List of trace amines

The human trace amines include: * Phenethylamines (related to catecholamines): ** Phenethylamine (PEA) ** ''N''-Methylphenethylamine (endogenous

isomer) ** Phenylethanolamine ** ''m''-Tyramine ** ''p''-Tyramine ** 3-Methoxytyramine ** ''N''-Methyltyramine ** ''m''-Octopamine ** ''p''-Octopamine ** Synephrine * Tryptamine While not trace amines themselves, the classical monoamines

, and

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

are all

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

s at the human TAAR1 receptor;

is a high-affinity

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

at human TAAR1. and 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 oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

s, is suggestive that they may be present as

chemical synapse Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

s at much higher concentrations than predicted by steady-state measures.

History

A thorough review of

trace amine-associated receptor Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerab ...

s that discusses the historical evolution of this research particularly well is that of Grandy.

Notes

References

{{Neurotransmitters TAAR1 agonists Amines Amphetamine Neurotransmitters Neurochemistry

List of trace amines

Concentrations

History

See also

Notes

References