Dopamine regulates colonic glial cell-derived neurotrophic factor secretion through cholinergic dependent and independent pathways

Background and PurposeGlial cell-derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine promotes GDNF release in astrocytes. We investigated the regulation by dopamine of colonic GDNF secretion.Experimental ApproachD1 receptor knockout (D1R-/-) mice, adeno-associated viral 9-short hairpin RNA carrying D2 receptor (AAV9-shD2R)-treated mice, 6-hydroxydopamine treated (6-OHDA) rats and primary enteric glial cells (EGCs) culture were used. Incubation fluid from colonic submucosal plexus and longitudinal muscle myenteric plexus were collected for GDNF and ACh measurements.Key ResultsD2 receptor-immunoreactivity (IR), but not D1 receptor-IR, was observed on EGCs. Both D1 receptor-IR and D2 receptor-IR were co-localized on cholinergic neurons. Low concentrations of dopamine induced colonic GDNF secretion in a concentration-dependent manner, which was mimicked by the D1 receptor agonist SKF38393, inhibited by TTX and atropine and eliminated in D1R-/- mice. SKF38393-induced colonic ACh release was absent in D1R-/- mice. High concentrations of dopamine suppressed colonic GDNF secretion, which was mimicked by the D2 receptor agonist quinpirole, and absent in AAV-shD2R-treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca2+ levels in primary cultured EGCs. Carbachol ( ACh analogue) promoted the release of GDNF. Quinpirole inhibited colonic ACh release, which was eliminated in the AAV9-shD2R-treated mice. 6-OHDA treated rats with low ACh and high dopamine content showed decreased GDNF content and increased mucosal permeability in the colon.Conclusion and ImplicationsLow concentrations of dopamine promote colonic GDNF secretion via D1 receptors on cholinergic neurons, whereas high concentrations of dopamine inhibit GDNF secretion via D2 receptors on EGCs and/or cholinergic neurons. image

Automated summary

This study found that dopamine promotes the secretion of colonic glial cell-derived neurotrophic factor (GDNF) via D1 receptors on cholinergic neurons, while high concentrations of dopamine inhibit GDNF secretion via D2 receptors on enteric glial cells (EGCs) and/or cholinergic neurons.