Despite a high prevalence with massive socioeconomic implications, fatigue per se, or as a symptom of a diagnosed condition, remains poorly understood. Much of the evidence available arises from measurement of biochemicals or proteins; alterations in which may be primary or secondary to the symptom, or indeed associated with another aspect of an underlying disease. However, an increasing body of evidence implicates an altered central 5-HT (5-hydroxytryptamine; serotonin) system. Although apparent inconsistencies are evident (for example, see Hartz and colleagues¹), elevated 5-HT neurotransmission appears most likely.^2–5 Numerous distinct receptors have evolved to transduce 5-HT signalling. The majority of these receptors (at least 13) are G protein coupled receptors (GPCRs) but, unusual for monoamine neurotransmitters, an additional receptor, the 5-HT₃ receptor, is a member of the cys-cys loop ligand gated ion channel superfamily; other members being the nicotinic acetylcholine receptor, the GABA_A receptor, and the glycine receptor.⁶ The 5-HT₃ receptor is predominantly expressed by central neurones and peripheral nerves and is known to mediate fast synaptic neurotransmission in the brain.

The clinical availability of 5-HT₃ receptor antagonists offers an opportunity to probe further for roles for this receptor. In …