The Role of Serotonin in Singultus: A Review

The use of dopamine receptor blockers for chronic singultus treatment is based—at least partially—on circular thinking: chlorpromazine is FDA-approved for hiccups, chlorpromazine is a neuroleptic, neuroleptics are dopamine receptor blockers, and therefore hiccup is due to dopaminergic dysfunction. Chlorpromazine interacts with high affinity with a multitude of receptors and ion channels. This promiscuity is the basis for many of the therapeutic effects and adverse drug reactions of this drug. While an involvement of dopamine is certain, it is by no means clear that dopaminergic dysfunction is the hallmark of singultus. The common denominator of most remedies for transient hiccup is their ability to activate the vagus nerve. Both afferent and efferent vagal activity and the central integration of the Xth cranial nerve function are modulated, inter alia, via serotonergic mechanisms; beneficial (therapeutic) effects for hiccup are to be expected from serotonin (5-HT) receptor subtype ligands that enhance vagal activity. Taken together, it appears that the ability to increase vagus output is mainly associated with 5-HT(1A), 5-HT(3), and 5-HT(7) agonists and with 5-HT(2C) antagonists. The plausibility of the serotonergic singultus hypothesis is examined against available pharmacokinetic, pharmacodynamic, and clinical data for a number of drugs.