Functional evaluation of the 5-HT2B receptor mediated effect of aripiprazole on the isolated rat stomach fundus

Objectives: The novel antipsychotic aripiprazole interacts with several serotonin (5-HT) receptor subtypes. Aripiprazole has partial agonist activity at 5-HT1A and is antagonist at 5-HT1B receptors. However, its effect at 5 HT2B receptors has not yet been characterized. Since the rat stomach fundus is uniquely rich in 5-HT2B receptors, it enables functional characterization of effects mediated by 5-HT2B receptors. Methods: Experiments were performed on male Wistar rats (250–350g; n=22). The stomach was removed and longitudinal strips (1.0–1.5×20mm) were dissected from the greater curvature of the fundus and suspended in 10ml tissue baths containing oxygenated (95% O2/5% CO2) Tyrode's solution at 37°C. To suppress prostaglandin mediated responses indomethacin (3.0µM) was also present. Experimental protocol: Auxotonic contractions were recorded using force transducers coupled to a chart recorder. After pre-incubation for 2h starting with a preload of 2g, the tension of the specimen was recorded and test substances were administered. The potencies of drugs were determined using sigmoidal curve fitting.

Results: Non-cumulative concentration-response curves were obtained for 5-HT (0.1nM-1µM), which evoked concentration-dependent contractile responses. The EC50 value for 5-HT was 12.7 nM. In subsequent experiments the strips were exposed to 100 nM 5-HT three times, then incubated with different concentrations of aripiprazole (1 nM-300 nM) increasing stepwise for 35min each and 5-HT administration was repeated. Aripiprazole itself did not affect the baseline tension but concentration-dependently reduced the contraction elicited by 5 HT. The IC50 value for aripiprazole was 126.9 nM.

Conclusion: Aripiprazole proved to be an antagonist at 5-HT2B receptors.