3B but which 3B and that's just one of the questions: the heterogeneity of human 5-HT3 receptors.

The 5-hydroxytryptamine 3 (5-HT3) receptor is expressed widely in the central and peripheral nervous systems, where it mediates or modulates a wide range of physiological processes. The receptor is targeted by drugs administered for nausea and/or emesis and irritable bowel syndrome and has been proposed as a potential drug target in various psychiatric disorders. The 5-HT3 receptor is a pentameric ligand-gated ion channel and belongs to the Cys-loop receptor family. In contrast to the immense heterogeneity characterizing other Cysloop receptors, native 5-HT3 receptors historically have been considered a much more homogenous receptor population. However, the recent discovery of additional 5-HT3 subunits and the dawning realization that central and peripheral 5-HT3 receptor populations might comprise several subtypes characterized by distinct functional properties has emphasized the complexity of human 5-HT3 receptor signaling. In this review potential implications of these findings and of the entirely new layer of interindividual diversity introduced to the 5-HT3 receptor system by genetic variations will be outlined.

5-HT3 receptors.

5-HT(3)-receptor antagonists are highly selective competitive inhibitors of the 5-HT(3)-receptor with negligible affinity for other receptors. They are potent, rapidly absorbed and easily penetrate the blood-brain barrier; metabolized by the cytochrome P450-system with half-life varying from 3-10 hours. The compounds investigated so far do not modify normal behaviour in animals or man and are well tolerated over wide dose ranges, the most common side effects being headache or constipation. Clinical efficacy was first established in chemotherapy-induced emesis (and then in radiotherapy-induced and post-operative emesis), where 5-HT(3)-receptor antagonists set a new standard of antiemetic efficacy and tolerability. The 5-HT(3) receptor antagonists, via a central and / or peripheral action, have been shown to reduce secretion and motility in the gut and possess clinical utility in irritable bowel syndrome, and possibly other visceral pain disorders. Their value in fibromyalgia is being evaluated. In preclinical behavioural assays they induce effects consistent with anxiolysis, improved cognition, anti-dopaminergic activity and use in drug abuse and withdrawal. There is some evidence that ondansetron may reduce alcohol consumption in moderate alcohol abusers but overall, 5-HT(3) receptor antagonists seem to be of limited use in psychiatric disorders: where effects have been seen, they seem to be unusually sensitive to dose and stage of disease. Nevertheless, their antiemetic potential has been of great benefit to cancer patients and the possible extension of their use to bowel disorders may yet fulfil their initial exciting promise.