Increased defaecation caused by 5-HT4 receptor activation in the mouse

The precursor to 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan, (5-HTP, 5-50 mg.kg-1) administered subcutaneously (s.c.) to conscious, fed mice caused a dose dependent increase in faecal pellet and fluid output. To avoid provoking watery diarrhoea, all experiments were performed using 5-HTP at 10 mg.kg-1. This dose caused maximal increases in the fluid content (471 +/- 41%) and number of formed faecal pellets defaecated (328 +/- 13% n = 25), 10 and 20 min respectively after administration, when compared to saline-treated mice. In both saline- and 5-HTP-treated mice methiothepin, ketanserin, mianserin and granisetron reduced defaecation at high s.c. doses (100 micrograms.kg-1 or 1000 micrograms.kg-1). The 5-HT4 receptor antagonists, DAU 6285 (endo-6-methoxy-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H-benzimidazole-1-carboxylate hydrochloride), SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) and SB 204070 ([1-butyl-4-piperidinylmethyl]-8-amino-7-chloro-1,4-benzodioxan -5- carboxylate), had no effects when administered s.c. to saline-treated mice, but dose-dependently inhibited the 5-HTP-evoked responses. Only SB 204070 at 1000 micrograms.kg-1 completely inhibited the responses to 5-HTP returning them to normal levels. We conclude that SB 204070 is a potent antagonist for the investigation of 5-HT4 receptor function in both normal and disturbed gastrointestinal activity.