Trace amines

Trace amines are a family of endogenous monoamine compounds including (3-phenylethylamine (PEA), p-tyramine (TYR), tryptamine (TRP) and octopamine (OCT). The trace amines share close structural similarity with the well known classical monoamine neurotransmitters such as dopamine (DA), norepinephrine (NE) and serotonin (5-HT). As their name suggests, trace amines occur in comparably much lower abundance than monoamine neurotransmitters. For historical reasons, other endogenous amine compounds which might share some structural similarities with PEA, TYR, TRP or OCT are not referred to as trace amines. 

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

The rate of synthesis is similar for trace amines and monoamine neurotransmitters, however, trace amines undergo a more rapid turnover due to their higher affinity to MAO and the lack of comparable cellular storage. Thus, the tissue concentration of trace amines in the vertebrate central nervous system is estimated to be in the range of 1-100 nM, depending on the trace amine and brain area, in contrast to micromolar concentrations of classic monoamine neurotransmitters. 

Due to their physicochemical properties trace amines can pass the cell membrane to a limited extent by passive diffusion, with the more lipophilic PEA and TRP crossing membranes more readily than the more polar amines TYR. and OCT. In spite of these features, trace amines show a heterogeneous tissue distribution in the vertebrate brain, and for TYR. and OCT storage in synaptic vesicles as well as activity-dependent release have been demonstrated. So far, trace amines have always been found co-localized with monoamine neurotransmitters, and there is no evidence for neurons or synapses exclusively containing trace amines. 

Although trace amine-selective receptors had been hypothesized for several decades and trace amine binding sites had been reported earlier, it was only... 

Trace Amines. Figure 1 The main routes of trace amine metabolism. The trace amines (3-phenylethylamine (PEA), p-tyramine (TYR), octopamine (OCT) and tryptamine (TRP), highlighted by white shading, are each generated from their respective precursor amino acids by decarboxylation. They are rapidly metabolized by monoamine oxidase (MAO) to the pharmacologically inactive carboxylic acids. To a limited extent trace amines are also A/-methylated to the corresponding secondary amines which are believed to be pharmacologically active. Abbreviations AADC, aromatic amino acid decarboxylase DBH, dopamine b-hydroxylase NMT, nonspecific A/-methyltransferase PNMT, phenylethanolamine A/-methyltransferase TH, tyrosine hydroxylase. 

Prior to the identification of specific receptors, the understanding of trace amine functions on the molecular level was limited to hypotheses mainly considering the following possibilities [1] (i) trace amines may serve... 

Trace Amines. Table 1 The trace amine-associated receptor (TAAR) family... 

The amphetamine-like properties of trace amines are best described for PEA which shares close structural similarity to amphetamine and can displace monoamine neurotransmitters from synaptic vesicles and trigger their release into the synaptic cleft by acting on the dopamine transporter. However, this effect is only observed at high, supra-physiological PEA concentrations and thus might not occur under physiological conditions. 

Invertebrates contain the trace amines OCT and TYR, which are the invertebrate counterparts of the vertebrate adrenergic transmitters NE and adrenaline. Invertebrate OCT and TYR occur at much higher... 

It shouldbe noted that current knowledge on the TAAR-mediated function of trace amines is mainly derived... 

D2 D2 dopamine receptor DAT dopamine transporter K+ potassium channel TAAR1 trace amine-associated receptor 1. 

Trace amines, most notably PEA, have been implicated in the etiology of depression. It has been suggested that trace amines stabilize mental functions within physiological limits, a hypothesis which might be in line with the assumed role of trace amines as... 

The postulation of a possible role of trace amines in the context of schizophrenia was kindled early on by the structural similarity between PEA and amphetamine. Symptoms such as hallucinations and paranoid episodes caused by a prolonged amphetamine intoxification are reminiscent of patients suffering from acute schizophrenia. Further support for a role of trace amines in the context of schizophrenia comes from clinical studies... 

Berry MD (2004) Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem 90 257—271... 

Borowsky B, Adham N, Jones KA, et al (2001) Trace amines identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci USA 98 8966-8971... 

Lindemann L, Hoener MC (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci 26 274-281... 

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

Boulton, AA, Baker, GB, Dewhurst, NG and Sandller, M (Eds) (1984) Neurobiology of the Trace Amines, Humana Press, Totowa, NJ. 

Usdin, E and Sandler, M (1976) Trace Amines and the Brain. Marcel Dekker, New York. 

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

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