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5-Hydroxytryptamine (5HT, serotonin) and dopamine (DA) are neurotransmitters in the central nervous system (CNS) that also have prominent peripheral actions. Although high concentrations of 5HT are present in the CNS, about 95% of all 5HT in the human body is located in the periphery, with high levels in enterochromaffin cells throughout the gastrointestinal (GI) tract and in storage granules in platelets. The highest concentrations of DA are found in the brain, but DA stores are also present peripherally in the adrenal medulla, in the plexuses of the GI tract, and in the enteric nervous system. Fourteen mammalian 5HT receptor subtypes, categorized into seven subfamilies, and five DA receptor subtypes, categorized into two subfamilies, have been delineated by structural and pharmacological analyses and are encoded by separate genes. For some receptors, alternative RNA splicing or editing creates additional heterogeneity; for example, over 30 isoforms of the 5HT2C receptor subtype arise from RNA editing. The identification of individual receptor subtypes has facilitated development of subtype-selective drugs and elucidation of actions of 5HT and DA at a molecular level. Increasingly, therapeutic goals are being achieved by using drugs that selectively target one or more of the subtypes of 5HT or DA receptors or that act on a combination of both 5HT and DA receptors.
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Abbreviations
AADC: aromatic L-amino acid decarboxylase
ADHD: attention-deficit/hyperactivity disorder
BBB: blood-brain barrier
COMT: catechol-O-methyl transferase
CGRP: calcitonin gene-related peptide
CSF: cerebrospinal fluid
DA: dopamine
DAG: diacylglycerol
DAT: dopamine transporter
L-DOPA: 3,4-dihydroxyphenylalanine
DOPAC: 3,4-dihydroxyphenylacetic acid
EPI: epinephrine
EPS: extrapyramidal symptoms
GABA: γ-aminobutyric acid
GI: gastrointestinal
GPCR: G protein-coupled receptor
GSK-3: glycogen synthase kinase 3
5-HIAA: 5-hydroxyindole acetic acid
HSDD: hypoactive sexual desire disorder
5HT: 5-hydroxytryptamine, serotonin
HVA: homovanillic acid
LSD: lysergic acid diethylamide
MAO: monoamine oxidase
MPP+: 1-methyl-4-phenylpyridinium
MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MSAA: multifunctional serotonin agonists and antagonists
NE: norepinephrine
NET: norepinephrine transporter
NO: nitric oxide
NSAID: nonsteroidal anti-inflammatory drug
NSS: neurotransmitter–sodium symporter
6-OHDA: 6-hydroxydopamine
PD: Parkinson's disease
PFC: prefrontal cortex
PKC: protein kinase C
PLC: phospholipase C
RLS: restless leg syndrome
SERT: serotonin transporter
SNRI: serotonin-norepinephrine reuptake inhibitor
SSRI: selective serotonin reuptake inhibitor
TAAR1: trace amine-associated receptor 1
TCA: tricyclic antidepressants
VMAT2: vesicular monoamine transporter 2
VNTR: variable number of tandem repeat
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HISTORICAL PERSPECTIVE
In the 1930s, Vittorio Erspamer began to study the distribution of enterochromaffin cells, which were stained with a reagent for indoles. The highest concentrations of these cells were found in GI mucosa, followed by platelets and the CNS. Subsequently, Irving Page and colleagues at the Cleveland Clinic isolated and characterized a vasoconstrictor substance released from platelets in clotting blood. This substance, named serotonin by Page, was identical to the indole, enteramine, isolated by Erspamer. Both enteramine and serotonin proved to be 5-hydroxytryptamine. Subsequent discovery of the biosynthetic and degradative pathways for 5HT and clinical presentation of patients with carcinoid tumors of intestinal enterochromaffin ...