Serotonin receptor search

A decline in trophic factors may contribute to aging, and a reduced level of hippocampal 5-HT, receptors in Alzheimer s disease would lead to decreased release of S-100 and increased levels of S-100 within cells (Griffin et al. 1989). The relevance of such changes to neuronal cell loss in the hippocampus and cortex remains to be established. The possibility that other serotonin receptor subtypes may also regulate the release of trophic factors remains to be determined (Whitaker-Azmitia and Azmitia 1991], as does the search for other neuronal growth factors (Zhou and Azmitia 1991]. However, such factors and the involvement of serotonin in their release may subsequently be shown to afford a site of drug action to attenuate cell decline and cognitive impairment. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

The hypothesis that serotonin dysfunction may play an important role in depression and the fact that tricyclic antidepressants are monoamine uptake inhibitors but also have a considerable affinity as antagonists for cholinergic, histaminergic and adrenergic receptors and thus may cause unwanted severe side-effects initiated the search for and development of selective serotonin uptake inhibitors. 

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