Trace amine receptors as targets for novel therapeutics: legend, myth and fact

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Abstract

Trace amines are attracting attention as neurotransmitters because they are believed to play a role in human disorders such as schizophrenia, depression, attention deficit disorder and Parkinson’s disease. Research to date is promising and confirms the need for continuing work to forge the way for new drug discovery.

Introduction

Trace amines (TAs) are endogenous amine compounds found in many organisms from plants, bacteria, insects and other invertebrates to mammals, including man (Figure 1). They are chemically related to biogenic amines and, for that reason, have engendered substantial attention in the scientific community. They are produced in the body but are also ingested in the diet in substances including chocolate, aged cheeses and wine [1]. The mythology that surrounds chocolate dates back to the classic Maya era, when coca was seen as the food of the Gods and was said to result in success with women [2]. An attractive hypothesis but still largely unsubstantiated. However, modifications of trace amines have recently been isolated from more earthly creatures such as from verongid sponges [3]. TAs can exert pronounced pharmacological effects in many species: they can affect uptake or release of catecholamines, or 5-HT activity, at nerve endings 4., 5., and they might also act as neuromodulators through direct actions on receptors for catecholamines or 5-HT 6., 7.. This review sketches and outlines a historical perspective and summarizes some of the most recent advances in the field, as well as highlighting therapeutic opportunities for drugs acting at these receptors.

Section snippets

Historical perspective

Consistent with the discovery of endogenous ligands for many mammalian receptors, the identification of pharmacological probes for the TA receptors was first described in the mid-1970s 8., 9.. Following a dormant period, the area has regained prominence with the identification of a novel family of G-protein-coupled ‘trace amine’ receptors 10.••, 11.••. The major TA ligands in mammals include tyramine (TYR), tryptamine (TRY), β-phenylethylamine (β-PEA) and octopamine (OCT) (Figure 1). They have

Discovery of G-protein-coupled receptors for trace amines

In spite of a huge body of work on TA ligands, their binding sites and their actions, little progress in understanding their role as possible neurotransmitters has been made in several decades. One rate-limiting factor in this endeavour was the inability to demonstrate specific receptors for these ligands in mammalian systems. Because the ligands clearly had action through other molecular targets, the search for their receptors fell by the wayside. This roadblock was breached by the first

Depression

Many, if not all, of the current drugs used for the treatment of depression have derived from the monoamine theory of depression [32]. Early observations that monoamine reuptake inhibitors and MAO inhibitors restored monoamine function following reserpine–induced depletion in animals led to the theory that drugs that restored monoamine function by increasing the levels of noradrenaline, 5-HT or dopamine were likely to be antidepressant. A counter hypothesis to the current dogma was subsequently

Attention-deficit hyperactivity disorder

Amphetamine potentiates catecholaminergic neurotransmission and striatal dopamine hyperreactivity (Figure 2). A close analogue of amphetamine, methylphenidate (Ritalin®), is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Its mechanism of action is believed to result from readdressing the neurochemical inbalance in dopamine neurotransmission that is thought to be closely associated with ADHD. Another structurally similar compound to amphetamine, β-PEA, has also been

Potential role in eating disorders

TA1 receptor mRNA has been detected in the arcunate and the paraventricular nuclei as well as the lateral hypothalamus. The cellular localization of TA1 receptor mRNA in these regions of the hypothalamus together with its moderate to high affinity across species for amphetamine, which is the most potent anorectic compound known in humans, supports a role for the TA1 receptor in the regulation of food intake. β-PEA is also an anorectic agent [51], and the highest endogenous levels of both β-PEA

Epilepsy

Albeit at high doses, β-PEA elicits seizures in animals similar to the tonic-clonic convulsions observed with pentylenetetrazol [54]. β-PEA-induced seizures are antagonized by benzodiazapines, diazepam and chlordiazepoxide, suggesting that the TA might interfere either directly or indirectly with GABAergic neurotransmission, and that the TA might play a role in some forms of human epilepsy [54].

Migraine

The myth and controversy surrounding the role of TAs in the pathogenesis of migraine is legendary in the annals of medical science [8]. It has been long known that TAs are present in a wide variety of foods, such as fish products, wine, beer, meat, cheese and other fermented foods that can trigger migraine attacks. The consumption of foods containing high concentrations of TAs can cause symptoms in some sensitive individuals, such as headaches, nausea, hypo- or hypertension, and cardiac

Conclusions

There are several factors that will facilitate the rekindling of the study of TAs as bona fide neurotransmitters. Obviously, elucidation of the genes encoding receptors for such ligands represents a major step forward [11••]. This groundbreaking work will allow the synthesis of selective compounds lacking monoamine-releasing activity, and thus provide novel pharmacological tools en route to drug discovery. Advances in imaging technology and its application to small animals, including knockout

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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    of special interest

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    of outstanding interest

References (58)

  • Q Cao et al.

    Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees

    Genomics

    (1997)
  • B Borowsky et al.

    Trace amines: identification of a novel family of mammalian G-protein-coupled receptors

    Neurosci. Abst.

    (2001)
  • C McClung et al.

    The trace amine tyramine is essential for sensitization to cocaine in Drosophila

    Curr. Biol.

    (1999)
  • B.A Davis et al.

    The trace amines and their acidic metabolites in depression–an overview

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1994)
  • A.A Boulton

    Trace amines and mental disorders

    Can. J. Neurol. Sci.

    (1980)
  • Wyatt RJ: In The Nature of Schizophrenia. Edited by Wynne LC, Cromwell RL, Matthysse S. New York: Wiley & Sons;...
  • K.L O’Malley et al.

    The human aromatic l-amino acid decarboxylase gene can be alternatively spliced to generate unique protein isoforms

    J. Neurochem.

    (1995)
  • T.R Vaughan

    The role of food in the pathogenesis of migraine headache

    Clin. Rev. Allergy

    (1994)
  • C Carpene et al.

    Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells

    Naunyn Schmiedebergs Arch. Pharmacol.

    (1999)
  • J.H Skerritt et al.

    Development of immunoassays for tyramine and tryptamine toxins of Phalaris aquatica L

    J. Agric. Food Chem.

    (2000)
  • Coe DS, Coe MD: In The True History of Chocolate. London: Thames & Hudson Ltd;...
  • C Lacy et al.

    New Moloka’iamine derivatives from an undescribed verongid sponge

    J. Nat. Prod.

    (2000)
  • G.B Baker et al.

    The effects of some indolalkylamines on the uptake and release of 5-hydroxytryptamine in rat striatum [proceedings]

    Br. J. Pharmacol.

    (1977)
  • Usdin E, Sandler M: Trace Amines and the Brain. New York: Dekker;...
  • Boulton AA: Trace amines: comparative and clinical neurobiology. In Experimental and Clinical Neuroscience. Edited by...
  • R.T Premont et al.

    Following the trace of elusive amines

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • B Borowsky et al.

    Trace amines: identification of a family of mammalian G protein-coupled receptors

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • E Kosa et al.

    Effects of beta-phenylethylamine on the hypothalamo-pituitary-adrenal axis in the male rat

    Pharmacol. Biochem. Behav.

    (2000)
  • D.P Holschneider et al.

    Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B

    Brain Res. Bull.

    (2001)

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