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The Dopamine-3 Receptor and Gastric Motility

94

Kashyap, Purna C., M.D.; Micci, Maria-Adelaide, Ph.D.; Pasricha, Pankaj Jay, M.D.

American Journal of Gastroenterology: September 2005 - Volume 100 - Issue - p S54
Supplement Abstracts Submitted for the 70th Annual Scientific Meeting of the American College of Gastroenterology: STOMACH
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Internal Medicine, University of Texas Medical Branch, Galveston, TX.

Purpose: Dopamine (DA) is a neurotransmitter present in large amounts in the gut. According to current concepts, DA inhibits acetylcholine release and gastrointestinal (GI) motility via neuronal D2 receptors (D2R). However, antagonists of this receptor have proven only partially useful in the relief of symptoms associated with various GI motility disorders. We hypothesized that other newly discovered dopamine receptors such as D3 (D3R) may also participate in dopaminergic control of gastric motility. The aim of this study was to investigate the effect of selective activation of the D3R on gastric motility in the rat.

Methods: Adult male Sprague-Dawley rats were used in the study. D3R expression was measured in rat pylorus protein extracts using a commercially available antibody (Zymed Lab, San Francisco, CA). The pyloric function was assessed by measuring the relaxation of pyloric strips in an organ bath in response to electrical field stimulation (EFS) in the presence of varying concentrations of D3R agonist (0.1, 1 and 10 mM). Gastric emptying was assessed by the phenol red method 20 minutes after feeding a non-nutrient methylcellulose meal to rats treated with varying doses of a selective D3R agonist (PD 128907 hydrochloride, 0.2, 0.5 or 1 mg/kg i.p.) or vehicle (PBS).

Results: Western blot analysis showed that the D3R is expressed in the rat pylorus. The D3R agonist significantly reduced EFS-induced relaxation of pyloric strips in an organ bath (P = 0.011 by two-way ANOVA). This effect was dose dependent, showing a greater decrease in relaxation with increasing doses of D3R agonists (1 μM vs control, P < 0.05; 10 μM vs control, P = 0.001). Gastric emptying was significantly delayed in rats injected with the D3R agonist in a dose-dependent fashion as compared to vehicle (see figure). [figure 1]

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Conclusions: Our data show for the first time that activation of D3R impairs pyloric relaxation and delays gastric emptying in the rat. These findings suggest a novel potential target for new pharmacological treatments for disorders of motility such as gastroparesis.

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