Acting on Serotonergic Systems

In periphery, activation — vasodilation, contraction of gastrointestinal, bronchial, and uterine smooth muscle, and platelet aggregation 

Found in area postrema, peripheral sensory and enteric nerves Mechanism of action activation opens ion channels (no second messengers) Drugs ondansetron and setrons  

Found in gastrointestinal smooth muscle and myenteric nerves Drug tegaserod 

Ergotamine acts as partial agonists at both a and 5HT2 receptors in the vasculature and possibly in the CNS. 

Vasoconstrictive actions to decrease pulsation in cerebral vessels may be relevant to acute actions of ergotamine during migraine attack. 

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Perturbation of the 5-HT system can elicit changes in a wide variety of behaviors. Furthermore, drugs that act on serotonergic neurons and their receptors are used to treat diseases such as depression, anxiety disorders and schizophrenia. Thus, 5-HT has been implicated in the regulation of many behaviors and physiological processes. The involvement of 5-HT in three areas - neuroendocrine function, circadian rhythms and feeding behavior - will be highlighted for illustrative purposes. 

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

Kobayashi H, Hasegawa Y, Ono H. Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems. EurJ Pharmacol. 1996 311 ... 

Magnoflorine was observed to decrease arterial blood pressure in rabbits and to induce hypothermia in mice. In addition, the alkaloid induced contractions in the isolated pregnant rat uterus and stimulated the isolated guinea pig ileum. Experiments with standard agents in these models suggest magnoflorine acts on the muscarinic and serotonergic systems, either directly or indirectly [302]. 

Local application of 8-OH-DPAT in the raph4 nuclei reduces the firing rate of serotonergic neurons by acting on the somatodendritic autoreceptor. This in turn leads to a reduction of the serotonergic neurotransmission, i.e. less serotonin is released in the synaptic cleft. It is not known which of the postsynaptic receptors is critically involved in the mediation of LLR. As far as we know, no local application studies have been performed in the major projection areas of the serotonin system. 

Tricyclic antidepressants act both presynaptically and postsynaptically on two major systems, the norader-nergic and the serotonergic. The actions of TCAs in each system will be discussed separately. Figure 23.2 shows an overall schematic of the receptor blockade of TCAs. 

Piribedil is a more direct DA agonist than is minaprine or CNS stimulants, lacking the effects of the former on the serotonergic and of the latter on the noradrenergic system. Like apomorphine, piribedil can stimulate presynaptic DA autoreceptors at low doses, but acts as a postsynaptic DA agonist at higher doses. Unlike apomorphine, which has pronounced emetic properties and has not been studied in depression, piribedil appeared to have modest antidepressant effects in patients with low pretreatment CSF levels of HVA and 5-HlAA and may be especially effective in those with particular poly-somnographic features [Kapur and Mann 1992]. 

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