Biogenic amines are a collection of endogenous molecules that play pivotal roles as\nneurotransmitters and hormones. In addition to the ââ?¬Å?classicalââ?¬Â biogenic amines resulting\nfrom decarboxylation of aromatic acids, including dopamine (DA), norepinephrine,\nepinephrine, serotonin (5-HT), and histamine, other biogenic amines, present at much\nlower concentrations in the central nervous system (CNS), and hence referred to\nas ââ?¬Å?traceââ?¬Â amines (TAs), are now recognized to play significant neurophysiological\nand behavioral functions. At the turn of the century, the discovery of the trace\namine-associated receptor 1 (TAAR1), a phylogenetically conserved G protein-coupled\nreceptor that is responsive to both TAs, such as Ã?²-phenylethylamine, octopamine,\nand tyramine, and structurally-related amphetamines, unveiled mechanisms of action\nfor TAs other than interference with aminergic pathways, laying the foundations for\ndeciphering the functional significance of TAs and its mammalian CNS receptor, TAAR1.\nAlthough, its molecular interactions and downstream targets have not been fully\nelucidated, TAAR1 activation triggers accumulation of intracellular cAMP, modulates\nPKA and PKC signaling and interferes with the Ã?²-arrestin2-dependent pathway via\nG protein-independent mechanisms. TAAR1 is uniquely positioned to exert direct\ncontrol over DA and 5-HT neuronal firing and release, which has profound implications\nfor understanding the pathophysiology of, and therefore designing more efficacious\ntherapeutic interventions for, a range of neuropsychiatric disorders that involve aminergic\ndysregulation, including Parkinsonââ?¬â?¢s disease, schizophrenia, mood disorders, and\naddiction. Indeed, the recent development of novel pharmacological tools targeting\nTAAR1 has uncovered the remarkable potential of TAAR1-based medications as\nnew generation pharmacotherapies in neuropsychiatry. This review summarizes recent\ndevelopments in the study of TAs and TAAR1, their intricate neurochemistry and\npharmacology, and their relevance for neurodegenerative and neuropsychiatric disease.
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