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INTRODUCTION

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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.

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ABBREVIATIONS

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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

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5-HYDROXYTRYPTAMINE

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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 proposal that serotonin ...

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