5-Hydroxytryptamine (5HT, serotonin) and DA are neurotransmitters in the CNS and also have prominent peripheral actions. 5HT is found in high concentrations in enterochromaffin cells throughout the GI tract, in storage granules in platelets, and throughout the CNS. The highest concentrations of DA are found in the brain; DA stores are also present peripherally in the adrenal medulla, in the plexuses of the GI, and in the enteric nervous system. Fourteen 5HT receptor subtypes and five DA receptor subtypes have been delineated by structural and pharmacological analyses. The identification of individual receptor subtypes has allowed for the development of subtype-selective drugs and the elucidation of actions of these neurotransmitters 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.
Abbreviations
AADC: aromatic L-amino acid decarboxylase
AC: adenylyl cyclase
ACh: acetylcholine
ADD: attention-deficit disorder
ADHD: attention-deficit/hyperactivity disorder
ALDH: aldehyde dehydrogenase
BBB: blood-brain barrier
CNS: central nervous system
COMT: catechol-O-methyl transferase
CSF: cerebrospinal fluid
DA: dopamine
DAG: diacylglycerol
DAT: dopamine transporter
L-dopa: 3,4-dihydroxyphenylalanine
DOPAC: 3,4-dihydroxyphenylacetic acid
ENT: equilibrative nucleoside transporter
EPI: epinephrine
EPS: extrapyramidal symptoms
FDA: Food and Drug Administration
FSIAD: female sexual interest/arousal disorder
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
LAT1: l-type amino acid transporter 1
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 agonist and antagonist
NE: norepinephrine
NET: norepinephrine transporter
NMDA: N-methyl-D-aspartate
NO: nitric oxide
NSS: neurotransmitter–sodium symporter
OCT: organic cation transporter
6-OHDA: 6-hydroxydopamine
PCPA: para-chlorophenylalanine
PD: Parkinson disease
PFC: prefrontal cortex
PH: phenylalanine hydroxylase
PKC: protein kinase C
PL_: phospholipase _, as in PLC
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 antidepressant
TH: tyrosine hydroxylase
TPH: tryptophan hydroxylase
VMAT2: vesicular monoamine transporter
VNTR: variable number of tandem repeats
In the 1930s, 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. Soon thereafter, Page and colleagues isolated and chemically characterized a vasoconstrictor substance released from platelets in clotting blood. This substance, named serotonin, was shown to be identical to the indole isolated by Erspamer. Subsequent discovery of the biosynthetic and degradative pathways for 5HT and clinical presentation of patients with carcinoid tumors of intestinal enterochromaffin cells spurred interest in 5HT. In the mid-1950s, the discovery that the pronounced behavioral effects of reserpine are accompanied by a profound decrease in brain 5HT led to the ...