Chapter 13

### INTRODUCTION

5-Hydroxytryptamine (5-HT, serotonin) and dopamine (DA) are neurotransmitters in the central nervous system (CNS) and also have prominent peripheral actions. 5-HT is found in high concentrations in enterochromaffin cells throughout the GI tract, in storage granules in platelets, and broadly throughout the CNS. 5-HT regulates smooth muscle in the cardiovascular system and the GI tract and enhances platelet aggregation. The highest concentrations of DA are found in the brain; dopamine stores are also present peripherally in the adrenal medulla and the transmitter is detectable in the plexuses of the GI tract and in enteric nervous system. DA modulates peripheral vascular tone to modulate renal perfusion, heart rate, and vasoconstriction/dilation. Fourteen 5-HT receptor subtypes and five DA-receptor subtypes have been delineated by pharmacological analyses and cDNA cloning. The availability of cloned receptors has allowed the development of subtype-selective drugs and the elucidation of actions of these neurotransmitters at a molecular level. Increasingly, therapeutic goals are being achieved by drugs that target selectively one or more of the subtypes of 5-HT or DA receptors, or that act on a combination of both 5-HT and DA receptors.

5-HT and DA are widely distributed in the animal and plant kingdoms. Several important laboratory invertebrate models have serotonergic and dopaminergic systems, including the fruit fly and nematode. 5-HT and DA are considered below in separate sections.

### 5-HYDROXYTRYPTAMINE

History. In the 1930s, Erspamer began to study the distribution of enterochromaffin cells, which stained with a reagent for indoles. The highest concentrations were found in GI mucosa, followed by platelets and the CNS. Soon thereafter, Page and colleagues isolated and chemically characterized a vasoconstrictor substance released from platelets in clotting blood. This substance, named serotonin, was shown to be identical to the indole isolated by Erspamer. Subsequent discovery of biosynthetic and degradative pathways for 5-HT and clinical presentation of patients with carcinoid tumors of intestinal enterochromaffin cells spurred interest in 5-HT. The gross effects of 5-HT, produced in excess in malignant carcinoid, gave some indication of the physiologic and pharmacologic actions of 5-HT, as did the identification of several naturally occurring and semi-synthetic tryptamine-like substances that were hallucinogenic and induced behavioral effects similar to those observed in carcinoid patients. In the mid-1950s, the discovery that the pronounced behavioral effects of reserpine are accompanied by a profound decrease in brain 5-HT led to the proposal that serotonin may function as a neurotransmitter in the mammalian CNS.

Sources and Chemistry. 5-HT [3-(β-aminoethyl)-5-hydroxyindole] is present in vertebrates, tunicates, mollusks, arthropods, coelenterates, fruits, and nuts. It is also a component of venoms, including those of the common stinging nettle and of wasps and scorpions. Numerous synthetic or naturally occurring congeners of 5-HT have pharmacological activity (see Figure 13–1 for chemical structures). Many of the N- and O-methylated indoleamines, such as N,N-dimethyltryptamine, are hallucinogens. Because these compounds are behaviorally active and might be synthesized by known metabolic pathways, they have ...

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