Trace Amines and Neurological Disorders

Potential Mechanisms and Risk Factors

Tahira Farooqui, Akhlaq A. Farooqui

• Publisher: Academic Press
• Year: 2016
• Print ISBN: 9780128036037
• eBook ISBN: 9780128036167
• Topic: Medicine
• Subtopic: Neurology

Trace Amines and Neurological Disorders: Potential Mechanisms and Risk Factors explores trace amines which, under normal conditions, are present in the mammalian brain and peripheral nervous tissues at very low (nanomolar) concentrations. However, in a diverse array of human pathologies ranging from substance abuse, depression, attention deficit hyperactivity disorder, eating disorders, schizophrenia, and other neurological and neuropsychiatric diseases, the levels of trace amines are unusually high with an imbalance in their functions. Furthermore, the rapid turnover of trace amines is evidenced by their dramatic increases following treatment with monoamine oxidase inhibitors (MAOI) or deletion of the MAO genes. This suggests that the concentration of trace amines may be considerably higher at neuronal synapses than predicted by steady-state measures, implicating some pathophysiological role. Therefore, understanding molecular mechanisms and developing selective agonists and antagonists for trace amine-associated receptors (TAARs) has become a good approach for treating these diseases. Although the effects of trace amines at low physiological concentrations in mammalian species have been difficult to demonstrate, they may serve to maintain the neuronal activity of other monoamine neurotransmitters by possessing postsynaptic modulatory effects, particularly dopamine and serotonin, within defined physiological limits. Such an effect of trace amines makes them ideal candidates for the development of novel therapeutics for a wide range of human disorders. This book presents up-to-date, cutting-edge, and comprehensive information on the link between trace amines and neurological disorders.- Focuses on recent findings on trace amines, providing insights into the functional significance, molecular mechanisms, and biological relevance of TAARS in neurological disorders- Edited work with chapters authored by leaders in the field from around the globe, the broadest, most expert coverage available- Provides cutting-edge research on trace amines-mediated signaling in vertebrate model systems

Section I

Introduction and Description of Trace Amines and Trace Amine-Associated Receptors

Outline

Chapter 1 Trace Amines: An Overview

Chapter 2 Methods of Trace Amine Analysis in Mammalian Brain

Chapter 3 Synthesis and Neurochemistry of Trace Amines*

Chapter 4 The Origin and Evolution of the Trace Amine-Associated Receptor Family in Vertebrates

Chapter 5 Differential Modulation of Adrenergic Receptor Signaling by Octopamine, Tyramine, Phenylethylamine, and 3-Iodothyronamine

Chapter 6 Effects of Trace Amines on the Dopaminergic Mesencephalic System

Chapter 7 Trace Amine-Associated Receptors in the Cellular Immune System

Chapter 8 Trace Amines and Their Receptors in the Control of Cellular Homeostasis

Chapter 9 Trace Amine-Associated Receptor 1 Modulation of Dopamine System

Chapter 10 Trace Amines as Intrinsic Monoaminergic Modulators of Spinal Cord Functional Systems

Chapter 11 Trace Amine-Associated Receptors: Ligands and Putative Role in the Central Nervous System

Chapter 12 β-Phenylethylamine Requires the Dopamine Transporter to Release Dopamine in Caenorhabditis elegans

Chapter 1

Trace Amines

An Overview

T. Roeder, Department of Zoology, Molecular Physiology, Kiel University, Kiel, Germany

Abstract

Trace amines (TAs) are usually defined as monoamines that fulfill a set of criteria; they do not act as classical neurotransmitters in vertebrates, they are present in only minute amounts in the brain and they have a sympathomimetic activity. Compounds such as phenylethanolamine, octopamine, tyramine, and synephrine are typical TAs. Recent deorphanization of bioamine receptors revealed that a number of different receptors in the mammalian brain react at nanomolar concentrations to these compounds.

Two TAs, the monoamines octopamine and tyramine, act as regular transmitters in invertebrates where they take the roles of epinephrine and norepinephrine that are absent in these organisms. The corresponding signaling systems comprising the amines and their receptors, attracted the interest of invertebrate neurobiologists as these systems combine surprising similarities with the architecture and functioning of vertebrate adrenergic systems with a highly specific receptor pharmacology, making them valid targets for specific insecticides.

Keywords

Octopamine; tyramine; TAAR; olfactory receptor; invertebrate

Outline

Introduction 3

Trace Amine-Associated Receptors 5

TAs in Invertebrates 6

Conclusion 7

References 8

Introduction

Biogenic amines such as epinephrine, norepinephrine, dopamine, serotonin, or histamine act as classical neurotransmitters or neuroactive compounds in the mammalian central nervous system. They are involved in the regulation of countless behaviors and take central roles for the proper functioning of the nervous system in general. Consequently, deregulation of aminergic signaling has been associated with a great number of neurological diseases such as Parkinson’s disease, schizophrenia, depression, and many others. Moreover, biogenic amine metabolism is central to our reward system, thus being centrally involved in almost all types of drug action and the development of addiction. Taking this importance into account, synthesis, storage, but also removal of these biogenic amines is tightly regulated in order to keep their concentrations in physiologically relevant ranges. Termination of aminergic signaling is usually achieved by the combined action of specific reuptake systems and their enzymatic degradation. A complex web of enzymatic activities is required to regulate synthesis of these bioactive amines, but it also produces intermediate products and so-called trace amines (TAs) (Fig. 1.1).^1–3

Figure 1.1 Biosynthesis pathways that give rise to TAs. Starting with the amino acids phenylalanine and tyrosine, two enzymes, the aromatic L-amino acid decarboxylase (AADC) and the biopterin-dependent aromatic amino acid hydroxylases (AAAH) produce phenethylamine, tyramine (AADC), and L-3,4-diidroxyphenylalanine (L-DOPA, AAAH), respectively. In invertebrates the tyrosine decarboxylase (TDC) produces tyramine from tyrosine. Moreover, the AADC also produces dopamine from L-DOPA. The phenylethanolamine N-methyltransferase (PNMT) catalyzes a number of different reactions including the production of N-methylphenethylamine from phenethylamine. Octopamine is, on the other hand, produced by the dopamine β-monooxygenase (DBH). In invertebrates, this is achieved by the tyramine β-hydroxylase (TβH). DBH is also responsible for the synthesis of norepinephrine from dopamine. Finally, the catechol-O-methyltransferase (COMT) converts dopamine into 3-methoxytyramine. TAs are marked by gray boxes and the enzymes that are required to produce tyramine and octopamine in invertebrates are shown in bold and italics.^1–3

In order to elicit physiological responses in target cells, sets of highly specific receptor molecules tailored to transmit only information carried by the specific biogenic amines are utilized. This set of receptors for biogenic amines has been used extensively as targets for countless therapeutic interventions using specific receptor agonists and/or antagonists. In addition to this handful of biogenic amines that are present at high levels in the mammalian central nervous system, other amines have been described that were found only in very low concentration. Consequently, these amines have been named TAs. As already pointed out, TAs are connected to the classical aminergic transmitter substances as they are usually produced within the same network of enzymes giving rise to these compounds. The very low concentration of TAs and the lack of information about specific receptor molecules led for several decades to the assumption that TAs have no particular transmitter or hormone function in the mammalian nervous system. This situation was changed only recently with the identification of a particular class of G-protein-coupled receptors named trace amine activated receptors (TAARs).⁴ The original definition of the term TAs was very vague; usually, they are defined as monoamines that fulfill a small set of criteria: (1) they do not act as classical neurotransmitters in vertebrates; (2) they are present in only minute amounts (mostly in the nanomolar range) in the mammalian brain; and (3) they usually have a sympathomimetic activity. Compounds such as phenylethanolamine, octopamine, tyramine, tryptamine, and synephrine are typical TAs (Fig. 1.1). Despite the fact that their particular physiological role was mostly neglected, deregulation of their concentration have been linked to numerous psychotic disorders such as depression, schizophrenia, migraine, or attention deficit hyperactivity disorder. The synthesis pathways that give rise to the different biogenic amines, as well as to the TAs listed above, are shown in Fig. 1.1.^1,2 Interestingly, both, conventional biogenic amines with an unequivocal transmitter function as well as the TAs share the same synthesis network comprising of proteins with the corresponding enzymatic activities. One early explanation for the presence of TAs was that they are unavoidable byproducts of these complex synthesis pathways.

More than 10 years ago, deorphanization of bioamine receptors revealed that a number of different receptors in the mammalian brain react at nanomolar concentrations to TAs. These receptors called trace amine-associated receptors (TAARs) revitalized the interest in studying the biology of TAs dramatically.⁴ A more detailed characterization of TAARs is found below.

The second highly interesting area of research where TAs have been focused on is their physiological role in invertebrates. Two of these TAs, octopamine, and tyramine, act as highly potent and highly important transmitter compounds in almost all invertebrates. In these animals they take the role of the classical aminergic neuroactive compounds epinephrine and norepinephrine. As for the TAARs, the role of TAs in invertebrates will be introduced below.

Trace Amine-Associated Receptors

In 2001, deorphanization of G-protein-coupled receptors revealed that TAs specifically activate some receptor molecules.^5,6 The first member of this family name trace amine-associated receptor 1 (TAAR1), was shown to be specifically activated by a set of TAs including phenylethanolamine (PEA) and tryptamine in the micro- to nanomolar range. TAAR1 was the founding member of a new family of GPCRs that shares significant similarities with members of the ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Quote
• Dedication
• List of Contributors
• Foreword
• Foreword
• Preface
• Acknowledgments
• Section I: Introduction and Description of Trace Amines and Trace Amine-Associated Receptors
• Section II: Trace Amines and Olfaction
• Section III: Trace Amines and Neurological Disorders
• Section IV: Perspective
• Index