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Thursday, April 21, 2011

Psychotropic Drugs that Modifythe Serotonergic System

Psychotropic Drugs that Modifythe Serotonergic System
Over a century ago, a substance was recognized in clotted blood which was
found to cause vasoconstriction. This substance was still present following
adrenalectomy therapy suggesting that it differed from adrenaline and
noradrenaline. Eventually, Rapaport, Green and Page in 1947, purified the
vasoconstrictor factor from serum and identified it as serotonin (‘‘serum
tonic’’). Independently of the American investigators, Erspamer and
colleagues in Italy had identified a substance they termed ‘‘enteramine’’
from the intestine. ‘‘Enteramine’’ was subsequently found to be identical to
serotonin and was subsequently synthesized by Hamlin and Fisher in 1951.
Chemically, serotonin or enteramine is the indoleamine 5-hydroxytryptamine
(5-HT).
Following the isolation and synthesis of serotonin in the early 1950s, there
has been increasing interest in the physiological function of this amine.
Initially, it was assumed that its main function was that of a peripheral
hormone because of the relatively high concentrations that were found in
the gastrointestinal tract and blood. Twarog and Page soon showed,
however, that it was also present in the mammalian brain thereby
suggesting that it may have a neurotransmitter role there. Interest in the
physiological role of serotonin in the central nervous system has
preoccupied neurobiologists since that time.
The detection of serotonin in nervous and non-nervous tissue was aided
by the development of the Falck–Hillarp histochemical technique, a method
whereby freeze-dried sections of tissue, when exposed to formaldehyde
vapour cause indoleamines to emit a yellow fluorescence. Dahlstrom and
Fuxe used this technique to show that the highest concentration of serotonin
in the brain is located in the raphe´ nuclei, projections from these cell bodies
ascending to the forebrain via the medial forebrain bundle. Descending
fibres were also shown to project to the dorsal and lateral horns and the
intermediolateral column of the spinal cord. Detailed observation of the
distribution of the serotonergic system in the brain became possible with the development of specific antibodies to the amine and the introduction of
autoradiographic methods for both the human and rodent brain.
For serotonin to be considered as a neurotransmitter, it was essential to
establish that it produced its physiological effects by activating specific
receptors located on the intestinal wall, platelet membrane or on nerve cells.
A major development occurred in 1957 when Gaddum and Picarelli
showed that the action of serotonin on the guinea-pig ileum could be
blocked by either phenoxybenzamine (dibenzyline) or morphine. These
investigators termed the two types of serotonin receptors on the intestinal
wall ‘‘D’’ (for dibenzyline) or ‘‘M’’ (for morphine) receptors, the ‘‘M’’ type
receptors being associated with the nerves supplying the intestine that
produced contraction of the smooth muscle by facilitating acetylcholine
release, while the ‘‘D’’ receptors were located on the smooth muscle wall.
More recently, it has been realized that the ‘‘D’’ receptors are widely
distributed in the body and coincide with 5-HT2 receptors which, when
activated by selective agonists, contract smooth muscle and aggregate
platelets. They also occur in synaptosomal membranes where they are
possibly associated with postsynaptic membrane structures. By contrast,
the ‘‘M’’ receptor has not been unequivocally identified in neuronal
membranes. However, increasing evidence now suggests that the
peripheral ‘‘M’’ receptor is identical to the 5-HT3 receptor in the brain.
Thus in a period of some 20 years, the distribution of serotonin in both
nervous and non-nervous tissue has been determined, many of its
physiological properties explained and the types of receptors upon which
it acts to produce its diverse physiological effects evaluated.

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