Blocking dopamine receptor 2 decreases gastrin levels in H. pylori-infected mice through increasing gastric somatostatin content.

Abstract

Long-term infection with Helicobacter pylori (H. pylori) leads to elevated serum gastrin levels, which are closely related to gastric cancer. Eradication of H. pylori to treat the high gastrin levels is increasingly challenged by antibiotic resistance. Dopamine (DA) receptor 1 (D₁R) is expressed on G cells in the gastric antrum. Parietal cells produce DA, which inhibits somatostatin (SOM) release through D₂R on D cells in the gastric mucosa. Whether targeted intervention in DRs can improve high gastrin levels after H. pylori infection remains to be explored. In this study, human gastric tissue, H. pylori-infected mice, D₁R and D₂R knockout mice, RT‒qPCR, ELISA, IHC, Western Blot, HE staining and ex vivo incubation of gastric mucosae were used. We found that H. pylori infection destroyed the mitochondria of parietal cells and reduced DA content in the gastric mucosa at 10 weeks after infection. Moreover, gastrin-positive cell numbers and serum gastrin levels were increased. D₁R, but not D₂R, was observed in G cells. DA promoted gastric gastrin secretion. Interestingly, both D1- and D2-like agonists mimicked the effect of DA on the gastrin secretion, which was antagonized by their antagonists. Blocking D₂R with domperidone or knocking out D₂R resulted in decreased gastrin-positive cell numbers and gastrin levels but increased SOM levels at 10 weeks after H. pylori infection. Our findings highlight the key regulatory effect of D₂R on gastrin secretion and elucidate the role of domperidone in reducing the elevated gastrin level associated with H. pylori infection.