Use of the pithed rat model to determine the relative potencies of 5-HT2A/2C receptor antagonists following acute intravenous and oral administration.

We investigated the usefulness of the pithed rat model to determine the relative potencies of 5-HT2A/2C receptor antagonists following acute intravenous and oral administration in inhibiting 5-HT-induced pressor responses. The 5-HT2A/2C receptor antagonists, pirenperone, ketanserin, and ritanserin, all dose-dependently inhibited 5-HT-induced pressor responses when administered either intravenously 5 min prior to commencing 5-HT injections or acutely via the oral route 30 min before pithing. All three compounds were found to be of comparable potency in inhibiting 5-HT-induced pressor responses when given i.v. (range of ID50s 3.7-27.5 micrograms/kg), whereas substantial differences became apparent after oral administration (range of ID50s 13.0-214.0 micrograms/kg), as reflected also by the p.o./i.v. ID50 ratios for the drugs. In conclusion, inhibition of 5-HT-induced pressor responses in the pithed rat preparation provides a reproducible and robust procedure in which comparisons can be made of relative potencies of 5-HT2A/2C receptor antagonists, not only by the intravenous route, but also following acute oral administration.