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

Background And Purpose: Glial 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 Approach: D receptor knockout (D R ) mice, adeno-associated viral 9-short hairpin RNA carrying D receptor (AAV9-shD R)-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 Results: D receptor-immunoreactivity (IR), but not D receptor-IR, was observed on EGCs. Both D receptor-IR and D 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 D receptor agonist SKF38393, inhibited by TTX and atropine and eliminated in D R mice. SKF38393-induced colonic ACh release was absent in D R mice. High concentrations of dopamine suppressed colonic GDNF secretion, which was mimicked by the D receptor agonist quinpirole, and absent in AAV-shD R-treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca levels in primary cultured EGCs. Carbachol ( ACh analogue) promoted the release of GDNF. Quinpirole inhibited colonic ACh release, which was eliminated in the AAV9-shD R-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 Implications: Low concentrations of dopamine promote colonic GDNF secretion via D receptors on cholinergic neurons, whereas high concentrations of dopamine inhibit GDNF secretion via D receptors on EGCs and/or cholinergic neurons.