Low‐Concentration Dopamine Potentiates Gastric Motility Through Activation of Dopamine D ₅ Receptor on Enteric Cholinergic Neurons

ABSTRACT Background Dopamine (DA) exerts complex concentration‐dependent effects on gastrointestinal motility. Although its inhibitory action through D2‐like receptors is well‐established, the mechanisms underlying its excitatory effects remain elusive. This study investigates the facilitatory effect of low‐concentration DA on gastric corpus motility and identifies the specific receptor and pathway involved. Methods Gastric motility recording, enzyme‐linked immunosorbent assay (ELISA), double‐labeled immunofluorescence, western blotting, M 2 /M 3 knockout mice, and D 5 R transgenic mice were used in this study. Results In isolated rat gastric strips, low‐dose DA (10–100 nM) enhanced spontaneous contractions, an effect mimicked by the D1‐like receptor agonist SKF38393 but not by the D2‐like agonist quinpirole. Immunofluorescence revealed that both D 1 R and D 5 R are co‐expressed with cholinergic neurons in the myenteric plexus. The prokinetic effects of DA and SKF38393 were abolished by tetrodotoxin or atropine, indicating neural and cholinergic dependence. Critically, using humanized D 5 R transgenic mice, gain‐of‐function (D 5 S390G ) and loss‐of‐function (D 5 F173L ) mutants, we established D 5 R as indispensable for the excitatory response: D 5 S390G mice showed enhanced contractility to DA and SKF38393, whereas D 5 F173L mice exhibited no response. Furthermore, in M 2 /M 3 muscarinic receptor knockout mice, DA and SKF38393 failed to enhance contractions, confirming the dependence on acetylcholine‐mediated smooth muscle activation. Conclusion These results identify a novel neurogenic pathway in which low‐concentration DA activates neuronal D 5 R on cholinergic enteric neurons, leading to acetylcholine release and M 2 /M 3 receptor‐mediated contraction of gastric smooth muscle. Our findings establish D 5 R as a critical mediator of dopamine‐induced gastric excitation in ex vivo preparations. Although the present study does not include in vivo experiments, these mechanistic insights suggest that D 5 R may represent a potential therapeutic target for gastroparesis and related motility disorders, warranting further validation in in vivo models.