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

Long-term infection with <i>Helicobacter pylori</i> (<i>H. pylori</i>) leads to elevated serum gastrin levels, which are closely related to gastric cancer. It is important to reduce serum gastrin levels after <i>H. pylori</i> infection. 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 <i>H. pylori</i> infection remains to be explored. In this study, human gastric tissue, <i>H. pylori</i>-infected mice, D₁R and D₂R knockout mice, RT-qPCR, enzyme-linked immunosorbent assay (ELISA), immunohistochemical (IHC), Western blot, and ex vivo incubation of gastric mucosae were used. We found that <i>H. pylori</i> infection destroyed the mitochondria of parietal cells and reduced DA content in the gastric mucosa at 10 wk 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 wk after <i>H. pylori</i> 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 <i>H. pylori</i> infection.<b>NEW & NOTEWORTHY</b> We report novel findings that blocking D₂Rs, not D₁Rs, decreased the number of gastric gastrin-positive cells and gastrin levels in <i>H. pylori</i>-infected mice. Gastric gastrin secretion induced by DA was indirectly mediated via D₂Rs, which suppressed SOM release. These results provide an experimental basis for local regulation of gastric gastrin secretion by DA through D₂Rs, offering a potential strategy for preventing and treating high gastrin levels in <i>H. pylori</i> infection.