1.4 Neurophysiology and Neurochemistry
39
Serotonin
The CNS contains less than 2 percent of the serotonin in the
body; peripheral serotonin is located in platelets, mast cells,
and enterochromaffin cells. More than 80 percent of all the
serotonin in the body is found in the gastrointestinal system,
where it modulates motility and digestive functions. Platelet
serotonin promotes aggregation and clotting through a most
unusual mechanism: The covalent linkage of serotonin mol-
ecules to small GTP-binding proteins, which can then activate
these proteins, is a process termed “serotonylation.” Peripheral
serotonin cannot cross the blood–brain barrier, so serotonin is
synthesized within the brain as well. Serotonin is synthesized
from the amino acid tryptophan, which is derived from the diet.
The rate-limiting step in serotonin synthesis is the hydroxyl-
ation of tryptophan by the enzyme tryptophan hydroxylase to
form 5-hydroxytryptophan (4-HT) (Fig. 1.4-7). Two isoforms
of tryptophan hydroxylase exist—one isoform is found mainly
in the periphery, whereas the second isoform is restricted to
the CNS.
Under normal circumstances, tryptophan concentration is rate limit-
ing in serotonin synthesis. Therefore, much attention has focused on
the factors that determine tryptophan availability. Unlike serotonin,
tryptophan is taken up into the brain by way of a saturable active car-
rier mechanism. Because tryptophan competes with other large neutral
amino acids for transport, brain uptake of this amino acid is determined
both by the amount of circulating tryptophan and by the ratio of tryp-
tophan to other large neutral amino acids. This ratio may be elevated
by carbohydrate intake, which induces insulin release and the uptake
of many large neutral amino acids into peripheral tissues. Conversely,
high-protein foods tend to be relatively low in tryptophan, thus lowering
this ratio. Moreover, the administration of specialized low tryptophan
diets produces significant declines in brain serotonin levels. After tryp-
tophan hydroxylation, 5-hydroxytryptophan is rapidly decarboxylated
by aromatic amino acid decarboxylase (an enzyme also involved in
dopamine synthesis) to form serotonin.
The first step in the degradation of serotonin is mediated by
monoamine oxidase type A (MAO
A
), which oxidizes the amino group
to form an aldehyde. MAO
A
is located in mitochondrial membranes and
is nonspecific in its substrate specificity; in addition to serotonin, it oxi-
dizes norepinephrine. The elevation of serotonin levels by MAO inhibi-
tors (MAOIs) is believed to underlie the antidepressant efficacy of these
drugs. After oxidation by MAO
A
, the resulting aldehyde is further oxi-
dized to 5-hydroxyindoleacetic acid (5-HIAA). Levels of 5-HIAA are
often measured as a correlate of serotonergic system activity, although
the relationship of these levels to serotonergic neuronal activity remains
unclear.
Catecholamines
The catecholamines are synthesized from the amino acid tyro-
sine, which is taken up into the brain via an active transport
mechanism (Fig. 1.4-8). Within catecholaminergic neurons,
tyrosine hydroxylase catalyzes the addition of a hydroxyl group
to the meta position of tyrosine, yielding l-dopa. This rate-
limiting step in catecholamine synthesis is subject to inhibi-
tion by high levels of catecholamines (end-product inhibition).
Because tyrosine hydroxylase is normally saturated with sub-
strate, manipulation of tyrosine levels does not readily affect the
rate of catecholamine synthesis. Once formed, l-dopa is rapidly
converted to dopamine by dopa decarboxylase, which is located
in the cytoplasm. It is now recognized that this enzyme acts
not only on l-dopa but also on all naturally occurring aromatic
l-amino acids, including tryptophan, and thus it is more prop-
erly termed aromatic amino acid decarboxylase. In noradren-
ergic and adrenergic neurons, dopamine is actively transported
into storage vesicles, where it is oxidized by dopamine
b
-
hydroxylase to form norepinephrine. In adrenergic neurons and
the adrenal medulla, norepinephrine is converted to epinephrine
by phenylethanolamine
N
-methyltransferase (PNMT), which is
located within the cytoplasmic compartment.
Two enzymes that play major roles in the degradation of catechol-
amines are monoamine oxidase and catechol-
O
-methyltransferase
(COMT). MAO is located on the outer membrane of mitochondria,
including those within the terminals of adrenergic fibers, and oxida-
tively deaminates catecholamines to their corresponding aldehydes.
Two MAO isozymes with differing substrate specificities have been
identified: MAO
A
, which preferentially deaminates serotonin and
Figure 1.4-7
Synthesis and catabolism of serotonin. (From Sadock BJ, Sadock
VA, Ruiz P.
Kaplan & Sadock’s Comprehensive Textbook of Psychia-
try
. 9
th
ed. Philadelphia: Lippincott Williams & Wilkins; 2009:68.)
