CENTRAL AND PERIPHERAL ADMINISTRATION OF SEROTONIN PRODUCES OPPOSITE EFFECTS ON MOUSE COLONIC PROPULSIVE MOTILITY

The effects of central or peripheral administration of serotonin on colonic expulsion time (CE) of a glass bead were evaluated after i.p. or free hand i.c.v. administration to mice. Serotonin (5-HT) caused an inhibition of CE when administered centrally but stimulated propulsion after i.p. administration. Several selective serotonin agonists were then tested. Inhibition after i.c.v. administration was produced by 8-OH-DPAT (5-HT1a), RU-24969 (5-HT1b), and 2-methyl serotonin (5-HT3), but not DOI (5-HT2) which augmented propulsion. Relative potencies for inhibition (ED50S) were RU (0.9-mu-g, 3.9 nM) > 8-OH-DPAT (3-mu-g, 9.1 nM) > 5-HT (7.8-mu-g, 20.1 nM) > 2-methyl serotonin (43-mu-g, 140 nM). After i.p. administration 5-HT stimulated propulsive motility (ED50 = 16.1-mu-g, 41.4 nM) while 8-OH DPAT (ED50 = 55-mu-g, 167 nM) and RU-24969 (ED50 = 54-mu-g, 236 nM) inhibited. DOI and 2-MS had no dose-related activity. The finding that several of the serotonin receptor agonists were capable of inhibiting propulsive motility either by i.p. or i.c.v. administration is a new finding and may help to explain drug-induced constipating activity in man. No selective agonist completely mimicked the effect of serotonin.