Catecholamine systems in the brain of vertebrates: new perspectives through a comparative approach.

The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2004.02501.x

Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators

DURING the past decade, the central neurotransmitter, dopamine (DA), has been much studied for it is known to be involved in certain human disease states, Parkinsonism1 preeminently, and rather more inferentially, schizophrenia2. DA is metabolised by monoamine oxidase (MAO)3, which catalyses the oxidative deamination of a wide range of monoamines4,5, including the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), and other amines such as tyramine, tryptamine and phenylethylamine (PEA). On the basis of animal studies with the inhibitors, clorgyline6, and later deprenil7, MAO has been classified into two types, A and B. By definition, type A is selectively inhibited by clorgyline and type B by deprenil. In general, type A acts on 5-HT6 while type B prefers PEA8. In the rat, DA is preferentially deaminated by MAOA9–11. It thus seemed paradoxical that, in the treatment of Parkinsonism, addition of the MAOB inhibitor, deprenil, to a DA-generating drug combination should produce further therapeutic benefit12. In this report, we reconcile these apparently conflicting observations by demonstrating that, as far as DA oxidation is concerned, man may be different from rat: in two sites we have investigated, platelet and brain, DA is preferentially deaminated by an enzyme with the characteristics of MAOB.

Dopamine is a monoamine oxidase B substrate in man

Another look at the monoamine oxidases and the monoamine oxidase inhibitor drugs

Classical biogenic amines (adrenaline, noradrenaline, dopamine, serotonin and histamine) interact with specific families of G protein-coupled receptors (GPCRs). The term 'trace amines' is used when referring to p-tyramine, beta-phenylethylamine, tryptamine and octopamine, compounds that are present in mammalian tissues at very low (nanomolar) concentrations. The pharmacological effects of trace amines are usually attributed to their interference with the aminergic pathways, but in 2001 a new gene was identified, that codes for a GPCR responding to p-tyramine and beta-phenylethylamine but not to classical biogenic amines. Several closely related genes were subsequently identified and designated as the trace amine-associated receptors (TAARs). Pharmacological investigations in vitro show that many TAAR subtypes may not respond to p-tyramine, beta-phenylethylamine, tryptamine or octopamine, suggesting the existence of additional endogenous ligands. A novel endogenous thyroid hormone derivative, 3-iodothyronamine, has been found to interact with TAAR1 and possibly other TAAR subtypes. In vivo, micromolar concentrations of 3-iodothyronamine determine functional effects which are opposite to those produced on a longer time scale by thyroid hormones, including reduction in body temperature and decrease in cardiac contractility. Expression of all TAAR subtypes except TAAR1 has been reported in mouse olfactory epithelium, and several volatile amines were shown to interact with specific TAAR subtypes. In addition, there is evidence that TAAR1 is targeted by amphetamines and other psychotropic agents, while genetic linkage studies show a significant association between the TAAR gene family locus and susceptibility to schizophrenia or bipolar affective disorder.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0706948

Trace amine-associated receptors and their ligands.

β-Phenylethylamine and serotonin were oxidatively deaminated by separate forms of monoamine oxidase of rat brain wimen studied in vitro . These forms, designated as type A and type B enzyme, have different characteristics. For example, type A enzyme deaminated serotonin, was sensitive to the drug clorgyline, was resistant to the drug deprenyl and was heat-stable. In contrast, type B enzyme deaminated β-phenylethylamine, was resistant to clorgyline, was sensitive to deprenyl and was heat-labile. Moreover, type A and type B enzyme activities could be partially separated by centrifugation on a continuous sucrose gradient. β-Phenylethylamine and serotonin are present in mammalian brain. We conclude from our studies that the amines of brain may be cataboblized by specific types of monoamine oxidase in vivo .

H. Y T. Yang

Papers

Beta-phenylethylamine: a specific substrate for type B monoamine oxidase of brain.