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Pharmacology of serotonin: what a clinician should know

Correspondence to: Professor F De Ponti, Department of Pharmacology, University of Bologna, Via Irnerio, 48, I-40126 Bologna BO, Italy; fabrizio.deponti@ unibo.it _ SUMMARY The pharmacology of serotonin (5-hydroxytryptamine or 5-HT) in the gut has been the centre of intense interest and research for several decades. Although it is now recognised that 5-HT is contained in intrinsic enteric neurones (where it works as a neurotransmitter), enterochromaffin cells of the mucosa are the main source (more than 90%) of the body’s 5-HT. In the gut, 5-HT is an important mucosal signalling molecule targeting enterocytes, smooth muscle cells, and enteric neurones. Application of exogenous 5-HT evokes so many responses that it is difficult to determine which are physiologically relevant. This bewildering range of effects is largely due to the presence of multiple receptor subtypes, which appear to be present on several classes of myenteric neurones, on smooth muscle cells, and on epithelial cells. 5-HT is thought to be involved in the pathophysiology of several clinical entities such as functional gut disorders (namely, irritable bowel syndrome), carcinoid diarrhoea, and chemotherapy induced emesis. In this review, the possible targets for pharmacological intervention are analysed in the light of the most recent advances of our understanding of the role of 5-HT in gut pathophysiology. Indeed, the recent regulatory interventions on cisapride (a 5-HT4 receptor partial agonist) and alosetron (a 5-HT3 receptor antagonist) have prompted a rethinking of our approaches to the pharmacological modulation of serotonergic pathways. In gut disorders, the most interesting targets for pharmacological intervention are: (1) the 5-HT receptor subtypes known to affect gut function such as those belonging to the 5-HT1, 5-HT3, 5-HT4, and 5-HT7 subtypes; and (2) the 5-HT reuptake mechanism which, apart from the central nervous system, is expressed in enteric neurones and enterocytes and is blocked by antidepressants.