Differential regulation of rat peripheral 5-HT2A and 5-HT2B receptor systems:: influence of drug treatment

Most studies of 5-HT2 receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT2A and 5-HT2C receptors); very few in vitro studies have addressed the peripheral receptors 5-HT2A and 5-HT2B. 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 muM) in the rat gastric fundus (5-HT2B receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT2A 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-HT2 receptors (5-HT2A and 5-HT2B) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT2 receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT2B receptors in rat gastric fundus are more sensitive to drug-induced regulation than the 5-HT2A rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer.