Abstract
Biogenic amines are a collection of endogenous molecules that play pivotal roles as neurotransmitters and hormones. In addition to the “classical” biogenic amines resulting from decarboxylation of aromatic acids, including dopamine (DA), norepinephrine, epinephrine, serotonin (5-HT), and histamine, other biogenic amines, present at much lower concentrations in the central nervous system (CNS), and hence referred to as “trace” amines (TAs), are now recognized to play significant neurophysiological and behavioral functions. At the turn of the century, the discovery of the trace amine-associated receptor 1 (TAAR1), a phylogenetically conserved G protein-coupled receptor that is responsive to both TAs, such as β-phenylethylamine, octopamine, and tyramine, and structurally-related amphetamines, unveiled mechanisms of action for TAs other than interference with aminergic pathways, laying the foundations for deciphering the functional significance of TAs and its mammalian CNS receptor, TAAR1. Although, its molecular interactions and downstream targets have not been fully elucidated, TAAR1 activation triggers accumulation of intracellular cAMP, modulates PKA and PKC signaling and interferes with the β-arrestin2-dependent pathway via G protein-independent mechanisms. TAAR1 is uniquely positioned to exert direct control over DA and 5-HT neuronal firing and release, which has profound implications for understanding the pathophysiology of, and therefore designing more efficacious therapeutic interventions for, a range of neuropsychiatric disorders that involve aminergic dysregulation, including Parkinson's disease, schizophrenia, mood disorders, and addiction. Indeed, the recent development of novel pharmacological tools targeting TAAR1 has uncovered the remarkable potential of TAAR1-based medications as new generation pharmacotherapies in neuropsychiatry. This review summarizes recent developments in the study of TAs and TAAR1, their intricate neurochemistry and pharmacology, and their relevance for neurodegenerative and neuropsychiatric disease.
Highlights
The classic biogenic amines, including dopamine (DA), norepinephrine, epinephrine, serotonin (5-HT), and histamine, are neurotransmitters that play vital roles in the regulation of a wide variety of neurophysiological, behavioral, and cognitive processes such as motor control, affect, motivation, learning, and memory
Mice engineered to overexpress trace amine-associated receptor 1 (TAAR1) showed unaltered spontaneous locomotor activity but hyposensitivity to amphetamine-induced psychomotor activity and catecholamine release in the nucleus accumbens (NAc) (Revel et al, 2012a). These findings suggest that TAAR1 may be constitutively active or tonically activated by ambient levels of endogenous amines to exert an inhibitory influence on monoaminergic neurotransmission
Neuropharmacological research into TAAR1, being the only member of the trace amine-associated receptors (TAARs) family that is phylogenetically conserved in mammals, has gained considerable momentum over the past decade, largely fuelled by the development of specific tools to unveil its neurophysiological and behavioral functions, most notably transgenic models, and direct ligands
Summary
The classic biogenic amines, including dopamine (DA), norepinephrine, epinephrine, serotonin (5-HT), and histamine, are neurotransmitters that play vital roles in the regulation of a wide variety of neurophysiological, behavioral, and cognitive processes such as motor control, affect, motivation, learning, and memory. Limited success has been achieved far in the symptomatic relief in these disorders, with direct manipulation of such neurotransmitter systems being in some instances associated with untoward side effects. In this regard, the DA system is a prototypical example. TAAR1 has proved to be an important modulator of the major biogenic amines and has begun to gain accumulated support as a promising target for medicinal development in a variety of neuropsychiatric disorders. In the current review we summarize the latest advancements in understanding the role of the TA system in the mammalian central nervous system (CNS), focusing on its pharmacology and neurochemistry and on the important implications of TAAR1 in the pathophysiology and treatment of neuropsychiatric disorders that involve aminergic dysregulation
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