History And Discovery

Serotonin (5-HT) is an indoleamine with wide distribution in plants, animals, and humans. Pioneering histochemistry by Falck et al. (1962) found that 5-HT was localized within specific neuronal pathways and cell bodies. These originate principally from two discrete nuclei, the medial and dorsal raphe. Across animal species, 5-HT innervation is widespread. Although regional variations exist, several limbic structures manifest especially high levels of 5-HT (A. H. Amin et al. 1954).

However, 5-HT levels in the central nervous system (CNS) represent only a small fraction of 5-HT found in the body (Bradley 1989). Because 5-HT does not cross the blood-brain barrier, it must be synthesized locally. 5-HT is released into the synapse from the cytoplasmic and vesicular reservoirs (Elks et al. 1979). Following release, 5-HT is principally inactivated by reuptake into nerve terminals through a sodium/potassium (Na+/K+) adenosine triphosphatase (ATPase)-dependent carrier (Shaskan and Snyder 1970). The transmitter is subsequently subject to either degradation by monoamine oxidase (MAO) or vesicular restorage. Abnormalities in central 5-HT function have been hypothesized to underlie disturbances in mood, anxiety, satiety, cognition, aggression, and sexual drives, to highlight a few. As described by Fuller (1985), there are several loci at which therapeutic drugs might alter 5-HT neurotransmission (Figure 13-1). The explosion of knowledge regarding the serotonergic system can largely be traced to the development of compounds, such as fluoxetine, that block the reuptake of this neurotransmitter.

FIGURE 13-1. Serotonin (5-HT) neuron showing the main steps in the life cycle of 5-HT and the sites at which drugs act.

Somatodendritic autoreceptor

Somatodendritic autoreceptor

cr-Methyl 5-HTP

5-HTP decarboxylase

Prevent 5-HT storage

Reserpine Tetra benazine

5-HT releasers p-Chlorophenylalanine Fenfluramine

Terminal auto receptor

Postsynaptic receptor

How To Win Your War Against Anxiety Disorders

How To Win Your War Against Anxiety Disorders

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