Trace Amines

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Sara Tomlinson, Glen B. Baker Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada

Synonyms

Arylalkylamines; Microamines Definition

Trace amines, which include b-phenylethylamine (PEA), tryptamine (T), phenylethanolamine (PEOH), the tyra-mines (TAs), octopamines (OAs), and synephrine (SYN) [some authors include N,N-dimethyltryptamine (DMT) in this list], are amines related structurally to, but present in the brain at much lower concentrations than, the classical neurotransmitter amines - dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT, serotonin).

Pharmacological Properties

History

The trace amines are so named because of their low absolute concentrations in the brain compared to the classical neurotransmitter amines DA, NA, and 5-HT; they are very similar structurally to these neurotransmitter amines (Fig. 1), but have much higher turnover rates, and PEA and T pass the ► blood-brain barrier readily.

In the 1960s through the 1990s, there was a great deal of interest in the trace amines in the central nervous system (CNS) as behavioral and pharmacological studies in animals and neurochemical measurements in body fluids from human subjects suggested their involvement in the etiology and pharmacotherapy of a number of psychiatric and neurological disorders, including depression, ► schizophrenia, ► phenylketonuria (PKU), ► Reye's syndrome, Parkinson's disease, ► attention deficit hyperactivity disorder (ADHD), ► Tourette's syndrome, epilepsy, and migraine headaches (Baker et al. 1993; Berry 2007). In the 1970s, there was a flurry of activity in trace amine research because of the development of a number of elegant, sensitive analytical techniques which facilitated their measurement in the brain. During the 1980s, there were binding studies done on possible receptors for the trace amines

Trace Amines. Fig. 1. Structures of some classical neurotransmitter amines and trace amines.

and there was also electrophysiological and behavioral research performed which suggested that these amines might act as neuromodulators for DA, NA, or 5-HT. There was a resurgence of interest in the trace amines in 2001, following reports of the discovery of a novel family of ► G proteincoupled receptors, some of which appear to be selectively activated by trace amines.

Synthesis, Catabolism, and Localization

The trace amines PEA, T, and TA are synthesized in neuron terminals by decarboxylation of precursor amino acids (phenylalanine, ► tryptophan, and tyrosine, respectively), catalyzed by the enzyme aromatic L-amino-acid decarboxylase (AADC), the same enzyme involved in the decarboxylation of l-DOPA and 5-hydroxytrytophan (5-HTP) in the synthesis of the ► catecholamines (DA, NA) and 5-HT, respectively. However, tyrosine hydrox-ylase and tryptophan hydroxylase are the rate-limiting enzymes in the synthesis of the catecholamines and 5-HT, while AADC is the major enzyme involved in the synthesis of PEA, T, and TA. Thus, alterations of AADC activity would be expected to have little effect on brain levels of DA, NA, and 5-HT while possibly markedly affecting the levels of trace amines (Berry 2007).

Tyramine is further metabolized to OA and PEA to PEOH by dopamine b-hydroxylase (DBH). Tyramine and OA have been proposed to function as neurotransmitters rather than neuromodulators in invertebrates. Octopa-mine can be further metabolized to synephrine by pheny-lethanolamine N-methyltransferase (PMNT) or related methyltransferases. The trace amines are all substrates for monoamine oxidase (MAO), with PEA being a preferred substrate for the MAO-B isoform. Abnormal levels of the resultant acid metabolites of the trace amines have also been reported in several psychiatric and neurological disorders by a number of researchers (Berry 2007; Boulton et al. 1984, 1985).

The trace amines are distributed heterogeneously throughout the brain, with the highest concentrations generally reported in the ► striatum or ► hypothalamus. Burchett and Hicks (2006) have provided a comprehensive review of their regional brain distribution and localization relative to catecholaminergic and serotoninergic neuronal systems in the brain. Although PEA, T, and TA have been shown to be present in synaptosomes, studies with ► reserpine and ► neurotoxins suggest that m- and p-TA may be stored in vesicles while PEA and T are not (see chapter by Juorio in Boulton et al. 1984). PEA and T appear to cross cell membranes passively, but there is some evidence for activity-dependent veratridine (a neu-rotoxin causing persistent activation of sodium ion channels) - induced release of m- and p-TA from striatal slices.

What Is the Function of the Trace Amines in the CNS?

It has long been known that trace amines such as PEA have amphetamine-like effects on the CNS when administered to rats or mice. However, given that the levels required to reach such effects were far beyond normal concentrations in brain, another role was believed to exist under physiological conditions. Researchers found mounting evidence that trace amines may play a neuromodulatory role in the CNS. The trace amines are known to inhibit reuptake of and stimulate release of NA, DA, and/or 5-HT; and in electrophysiological studies, several trace amines have been shown to potentiate the actions ofthe classical mono-amine neurotransmitter amines DA, NA, and/or 5-HT by altering the receptor sensitivity to these neurotransmitter amines, suggesting that the trace amines serve to maintain the activity of the classical monoamine neurotransmitters within defined physiological limits (Berry 2007). PEA has also been reported to stimulate acetylcholine release by activating glutamatergic signaling pathways, and PEA and p-TA have been demonstrated to depress GABAb receptor-mediated responses in dopaminergic neurons. In the 1980s, specific and saturable binding sites for radiolabeled PEA, T and p-TA were reported, suggesting that these amines might have a role independent of the classical neurotransmitter amines. Burchett and Hicks (2006) have suggested four kinds of trace amine activity in the CNS: cotransmitters released with the catecholamines or 5-HT; transmitters with their own receptors; false transmitters at catecholamine receptors; and neuromodulators.

Receptors

There has been a resurgence of interest in trace amines in the past few years with the publication of papers in 2001 on the discovery and cloning of a unique family of G proteincoupled receptors, some of which are selectively activated by trace amines (Borowsky et al. 2001; Bunzow et al. 2001), although the mechanisms by which the trace amines activate these receptors are not yet fully defined (Lindemann and Hoener 2005). However, to date only two members of the family have been demonstrated to be responsive to trace amines, and endogenous ligands other than the trace amines which have been proposed include O-methyl metabolites of catecholamines, thyronamine metabolites ofthyroid hormones, and imidazoline ligands including b-carbolines (Berry 2007; Bunzow et al. 2001; Grandy 2007).

The trace amine-associated receptor (TAAR) family consists of three subgroups (TAAR1-4, TAAR5, and

TAAR6-9) which are phylogenetically and functionally distinct from other G protein-coupled receptor families and from invertebrate OA and TA receptors (Lindemann and Hoener 2005). Genes for TAARs have been discovered in humans, chimpanzees, rats, and mice. There are marked interspecies differences in the distribution of the TAARs. For example, there are as many as 18 TAARs in the rodent genome and 9 in the human genome. This variability has led some researchers to suggest that these receptors are linked in an intricate way to species-specific functioning (Berry 2007). In humans, all TAAR genes are located in a narrow region in the locus 6q23.1, which has also been linked to schizophrenia and ► bipolar disorder. Recent studies on TAAR1 knockout mice suggest that the TAAR1 is a regulator of dopaminergic neurotransmission and that such mice may represent a useful model for development of drugs for treatment of some positive symptoms of schizophrenia. Studies by Sotnikova et al. (2008) in TAAR1-knockout (KO) mice, DA transporter (DAT)-KO/TAAR1-KO mice, and TAAR1-deficient/DA-deficient mice suggested that the TAAR1 is involved in tonic inhibitory actions on locomotor activity, and the authors proposed that blockade of the TAAR1 by antagonists may represent a novel way to enhance the antipar-kinsonian effects of L-DOPA.

Several amphetamines [► amphetamine, ► MDMA (Ecstasy), DOI, 4-hydroxyamphetamine] are relatively potent agonists at the TAAR1 receptor, as are ergome-trine, dihydroergotamine, LSD, and the anti-Parkinson agents ► bromocriptine and lisuride, and inhibitors of the DA transporter. Interestingly, the trace amine p-TA has been demonstrated to be necessary for ► sensitization to ► cocaine to occur in Drosophila. These findings are of interest because it is possible that the TAAR1 may be a mediator of at least some of the effects of drugs of abuse, providing a possible future target for treatment of drug abuse. It is also of interest that several biogenic amine antagonists, including phentolamine, tolazoline, cypro-heptadine, dihydroergotamine, ► metergoline, and

► chlorpromazine, as well as ► nomifensine and MPTP, act as agonists at the TAAR1 (Grandy 2007).

Involvement in Psychiatric and Neurologic Disorders: Neurochemical Studies

Several studies looking at the levels of trace amines and/or their acid metabolites in body fluids of patients with psychiatric or neurological disorders found potential links to

► depression, ► bipolar disorder, ► schizophrenia,

► Reye's syndrome, ADHD, ► Tourette's syndrome, and

► phenylketonuria (Baker et al. 1993; Berry 2007; Boulton et al. 1984, 1985), although these studies are not without controversy. Increased PEA levels have been reported in mania while depressed states have been found to be associated with deficits in PEA and the acid metabolites of OA and TA. Links between paranoid schizophrenia and increased PEA excretion have been proposed as well. Decreased body fluid levels of PEA have been reported in Parkinson's disease. Tryptamine levels in urine have also been reported to be increased in schizophrenics and to correlate with disease severity, and plasma levels of the p-TA metabolite p-hydroxyphenylacetic acid have been reported to be decreased in schizophrenia. Increased brain levels of PEA have been reported in phenylketon-uria. Evidence to date from several research groups suggest decreased urinary PEA in ADHD and Tourette's syndrome; there is also evidence for decreased PEA levels in brain and plasma in ADHD and for decreased urinary levels of m- and p-TA and indole-3-acetic acid (the major metabolite of T) in Tourette's syndrome. Animal studies and limited data in humans suggest that elevated PEA may be associated with elevated stress and anxiety. Elevations of TA and OA have been reported in hepatic enceph-alopathy and Reye's syndrome. High doses of PEA can induce seizures in mice, and this effect can be antagonized by, ► benzodiazepines, suggesting an interaction with the GABA system. Other studies have suggested that PEA modulates glutamatergic and GABAergic systems. It is of interest that the gene for AADC, the major enzyme involved in the synthesis of the trace amines, is located in the same region of chromosome 7p that has been suggested as a susceptibility locus for ADHD; 7p has also been linked to nicotine dependence.

The effects of drugs used to treat psychiatric illnesses provide further support for the importance of trace amines. It is known that ► monoamine oxidase inhibitor ► antidepressants such as ► phenelzine and ► tranylcy-promine cause a much greater increase in brain levels of trace amines than classical neurotransmitters such as 5-HT and NA, and increases in the brain levels of PEA have been reported with ► tricyclic antidepressants and ECT. l-Deprenyl (► selegiline) and rasagiline are used in the treatment of ► Parkinson's disease, and because they are selective inhibitors of MAO-B, they cause a marked increase in the brain levels of PEA relative to other amines. The antipsychotics ► chlorpromazine, ► fluphenazine, and ► haloperidol have been shown in studies in rodents to decrease striatal p-TA levels acutely; similar studies with PEA have found that antipsychotics increase the rate of PEA accumulation in the striatum (see chapters in Boulton et al. 1984, 1985 for studies on these drug effects).

Summary

Behavioral, pharmacological, and neurochemical studies in animals as well as investigations in body fluids of humans have long suggested that trace amines such as PEA, T, TA, and OA may be involved in the etiology and/ or pharmacotherapy of a number of psychiatric and neurologic disorders. There has always been debate about whether the trace amines have a neurotransmitter role. Although there is good evidence that OA may be a neuro-transmitter in invertebrates, electrophysiological research has suggested that trace amines act as neuromodulators in the human brain, with their activity related intimately to the classical neurotransmitters amines DA, NA, and 5-HT.

There has been a marked resurgence of interest in the trace amines since reports in 2001 of a unique family of G protein-coupled receptors, some of which are selectively activated by trace amines. These receptors, now termed TAARs, are helping to explain the possible role ofthe trace amines in the CNS (including their interactions with classical neurotransmitters), the effects of other compounds which may be endogenous ligands at these receptors, and the actions of a number of drugs of abuse and may prove to be very useful in discovering more selective future drugs for the treatment of psychiatric and neurological disorders.

Boulton AA, Baker GB, Dewhurst WG, Sandler M (eds) (1984) Neurobiology of the trace amines. Humana Press, Clifton Boulton AA, Bieck PR, Maitre L, Riederer P (eds) (1985) Neuropsycho-pharmacology of the trace amines: experimental and clinical aspects. Humana Press, Clifton Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI et al (2001) Amphetamine, 3,4-methylenedioxymetham-phetamine, lysergic acid diethylamide, and metabolites of the cate-cholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol 60:1181-1188 Burchett SA, Hicks TP (2006) The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain. Prog Neurobiol 79:223-246 Grandy DK (2007) Trace amine-associated receptor 1 - family archetype or iconoclast? Pharmacol Ther 116:355-390 Lindemann L, Hoener MC (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci 26:274-281 Sotnikova TD, Zorina OI, Ghisi V, Caron MG, Gainetdinov RR (2008) Trace amine associated receptor 1 and movement control. Parkin-sonism Relat Disord 14:S99-S102

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