system, the hematological system, and the central nervous system. Because of this diverse
participation in many physiological processes, 5-HT active agents exert pharmacological
effects in the plethora of disease states, including sleep disorders, modulation of circadian
rhythms, eating disorders, depression, stimulation of bowel activity, migraine headache,
and platelet aggregation (including the role of platelets in stroke and heart attack).
The serotonergic neuronal system in the CNS is rather restricted, localized by fluores-
cence histochemistry and autoradiography to the raphe region of the pons and brainstem,
and projecting inferiorly to the medulla and spinal cord. The functional correlations of
serotonergic neurons are equally difficult to elucidate, but work in this area has been
helped by neurotoxins such as 5,6- and 5,7-dihydroxytryptamine, which destroy seroton-
ergic neurons in the same way that 6-hydroxydopamine atrophies adrenergic networks.
4.5.1 Serotonin MetabolismSerotonin metabolism, shown in figure 4.9, bears considerable similarities to that of the
catecholamines. Serotonin itself is transformed in the pineal gland into melatonin
(4.110), a hormone active in lightening skin pigmentation and suppressing the function
of the female gonads. The β-adrenergic innervation of the pineal gland is governed by
light: darkness increases cAMP formation and activation of the acetyltransferase
enzyme, resulting in increased melatonin synthesis. Although situated near the thala-
mus, the pineal gland is not part of the CNS; it is a peripheral organ as far as the
blood–brain barrier is concerned.
Serotonin is stored in synaptic vesicles and blood platelets in the form of an ATP com-
plex in the ratio of 2:1. Very little is known about its release, but exocytosis is the
assumed mechanism. The released neurotransmitter is deactivated primarily by reuptake,
but a significant amount is metabolized by MAO to the corresponding indoleacetic acid.
4.5.2 Serotonin ReceptorsThe characterization and classification of serotonergic receptors is continually under-
going rapid and controversial development, and has to be viewed as “in progress.” Over
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