Serotonin: A Mediator of the BrainGut ConnectionDoe-Young Kim,
M.D., and Michael Camilleri, M.D.Gastroenterology Research Unit,
Mayo Clinic and Mayo Foundation, Rochester, Minnesota
INTRODUCTION
Serotonin is an important brain neurotransmitter that isrelevant
to depression, migraine, and other neuropsychiatricillnesses. It
has been estimated that about 95% of serotoninis found in the GI
tract. Research about gut serotonin lagsbehind that in brain and,
similarly, the application of sero-tonergic agents to gut disorders
is still in its infancy. In thepast decade, serotonin antagonists
have been used in che-motherapy-induced emesis, and some serotonin
agonists areprescribed as prokinetic drugs. In irritable bowel
syndrome(IBS), serotonergic antidepressants have been used in
clin-ical practice, but they also modulate central
cholinergic,adrenergic, or dopaminergic systems. Selective
serotoninagonists and antagonists are being proposed for treatment
ofgut disorders, primarily because of their direct effects on
thegut rather than any central effects. Our goal in this review
isto provide the reader with an understanding of the
basicphysiology of serotonin (a mediator of the braingut
con-nection), serotonin receptor subtypes, the role of serotoninin
diseases of the gut, and the potential role of agonists
andantagonists in GI clinical therapeutics.
In summarizing this information for readers with an interestin
gastroenterology, we wish to bear witness to the pioneeringwork and
consistent contributions over almost four decades ofa pre-eminent
neuroscientist, Dr. Michael D. Gershon, whofirst proposed that
serotonin fulfilled the criteria for a neuro-transmitter in the GI
tract and, subsequently, contributed to thecharacterization of
receptor subtypes that have led to noveltherapeutic agents in the
field of neurogastroenterology.
WHAT IS SEROTONIN?
Serotonin (5-hydroxytryptamine, 5-HT) is
3-(b-aminoeth-yl)-5-hydroxyindole. Like histamine, it is widely
distributedin the animal and plant kingdoms. It occurs in
vertebrates,tunicates, mollusks, arthropods, and coelenterates, and
inedible fruits and nuts. It is also present in numerous
venoms,including those of the common stinging nettle and in
waspsand scorpions (1).
WHERE IS SEROTONIN IN THE BODY?
Serotonin Synthesis and MetabolismAbout 95% of the serotonin in
the body is found in the GItract, where it has been estimated that
the total serotonin
content is about 10 mg; 90% is in enterochromaffin cells and10%
in enteric neurons. The remainder of 5-HT (5%) isfound in the
brain. Virtually all of the serotonin in the bloodis derived from
the GI tract (2, 3). Serotonin is present inenteric nerves (49) and
is synthesized in the enteric ner-vous system (5, 10). Serotonergic
neurons constitute about2% of all myenteric neurons (11). Serotonin
is released fromthe bowel when enteric nerves are stimulated (8).
Serotoninis also an important constituent of platelets, and it
partici-pates in aggregation of platelets and coagulation of blood
(2,3). Serotonin is easily released by agitation and lysis
ofplatelets, and this renders plasma measurements of
serotonininaccurate.
Serotonin is synthesized from the essential amino acidtryptophan
by two enzymatic steps. First, hydroxylation oftryptophan by the
enzyme tryptophan hydroxylase (the ac-tivity of which is
rate-limiting) produces 5-hydroxytrypto-phan. The second enzymatic
step is decarboxylation of5-hydroxytryptophan by the enzyme
aromatic L-amino aciddecarboxylase producing serotonin (12) (Fig.
1). Serotoninin tissues can be very rapidly metabolized, mainly as
a resultof the activity of monoamine oxidase. In the kidney and
theliver, the enzymes, monoamine oxidase and aldehyde
dehy-drogenase convert 5-HT to 5-hydroxyindole acetic acid
(5-HIAA), which is excreted in the urine. Approximately 210mg of
5-HIAA is excreted daily by the normal adult as aresult of the
metabolism of endogenous 5-HT. The gut hasan inactivating
mechanism, a transporter-mediated uptake,which is present both in
the mucosa and in nerves of theenteric nervous system (7,
1315).
It has been suggested that there is a gender difference
inserotonin synthesis in human brain (16, 17). Nishizawa et al.(16)
measured the rate of serotonin synthesis in human brainwith
positron emission tomography (PET) and found thatthe mean rate of
serotonin synthesis in normal male subjectswas higher than in
normal female subjects. They speculatedthat manicdepressive
disorder, which is characterized bylow serotonin synthesis, is more
frequent in women becauseof the lower 5-HT synthesis rate in women.
There is con-tradictory information from a study that showed
femalesynthesis rates in the brain to be 20% higher than those
ofmen (17). Moreover, it is still unknown whether there is alsoa
gender difference in serotonin synthesis rates in the GItract, or
whether differences in brain or gut synthesis ratesinfluence gut
function.
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No. 10, 2000
2000 by Am. Coll. of Gastroenterology ISSN
0002-9270/00/$20.00Published by Elsevier Science Inc. PII
S0002-9270(00)01970-5
