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-hydroxytrypt-amine (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
Fundamentals of Psychopharmacology. Third Edition. By Brian E. Leonard © 2003 John Wiley & Sons, Ltd. ISBN 0 471 52178 7
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. The main serotonergic pathways in the human brain are illustrated in Figure 6.1.
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