Differential regulation of rat peripheral 5-HT(2A) and 5-HT(2B) receptor systems: influence of drug treatment.

Most studies of 5-HT(2) receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT(2A) and 5-HT(2C) receptors); very few in vitro studies have addressed the peripheral receptors 5-HT(2A) and 5-HT(2B). The aim of this investigation was to compare the possible short- and long-term processes regulating these peripheral receptors in the rat. The in vitro contractile response elicited by serotonin (5-HT, 10 micro M) in the rat gastric fundus (5-HT(2B) receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT(2A) receptor system), which was more stable, slower and sustained. To characterize drug-receptor interactions, cumulative concentration/response curves (CCRCs) for 5-HT were constructed ex vivo for rat tissues treated with drugs acting at these receptors. Rats were examined 4 or 24 h after a single, i.p. administration of (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)DOI, 1 or 2.5 mg/kg], clozapine, cyproheptadine or rauwolscine (10 mg/kg), 48 h after a single i.p. administration of (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine (10 mg/kg) or 24 h after the last of with 15 daily i.p. administrations of (+/-)DOI (1 or 2.5 mg/kg), clozapine, cyproheptadine or rauwolscine (10 mg/kg). In the aorta, E(max) (the maximum response elicited by 5-HT) was unchanged 4 h after a single dose of any of the drugs tested. However, 24 h after a single dose, E(max) was lower in animals treated with (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine than in controls, whilst 48 h after a single dose of (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine there was no difference in E(max) between experimental and control animals. After chronic treatment with (+/-)DOI (2.5 mg/kg), clozapine and cyproheptadine, E(max) was lower than in controls. In the gastric fundus, E(max) 4 h after a single dose of each drug was lower than in controls, and the response recovered by 24 or 48 h. Following chronic treatment, E(max) was significantly lower than in controls for each drug used. These findings suggest first, that regulation of peripheral 5-HT(2) receptors (5-HT(2A) and 5-HT(2B)) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT(2) receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT(2B) receptors in rat gastric fundus are more sensitive to drug-induced regulation than the 5-HT(2A) rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer.