Neuroendocrine evidence that (S)-2-(chloro-5-fluoro-indol-/-yl)-1-methylethylamine fumarate (Ro 60-0175) is not a selective 5-hydroxytryptamine_2C receptor agonist

The 5-hydroxytryptamine_2A and _2C (5-HT_2A and 5-HT_2C) receptors are so closely related that selective agonists have not been developed until recently with the advent of (S)-2-(chloro-5- fluoro-indol-/-yl)-1-methylethylamine fumarate (Ro 60-0175), a putatively selective 5-HT_2C receptor agonist. In the present study, Ro 60-0175 was used to analyze the importance of 5-HT_2C receptors in hormone secretion. Injection of Ro 60-0175 (5 mg/kg s.c.) produced a maximum increase in plasma levels of adrenocorticotrophic hormone, oxytocin, and prolactin at 15 min postinjection and a maximum increase in plasma corticosterone levels at 60 min postinjection. Ro 60-0175-mediated increases in plasma hormone levels were dose-dependent (corticosterone ED₅₀ 2.43 mg/kg; oxytocin ED₅₀ = 4.19 mg/kg; and prolactin ED₅₀ 4.03 mg/kg). To assess the role of 5-HT_2C and 5-HT_2A receptors in mediating the hormone responses to Ro 60-0175, rats were pretreated with the 5-HT_2C antagonist 6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbonyl] indoline (SB 242084) or 5-HT_2A antagonists (±)-2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol) (MDL 100,907) before injection of Ro 60-0175 (5 mg/kg s.c.). Neither SB 242084 (0.1, 0.5, 1, and 5 mg/kg i.p.) nor MDL 100,907 (1, 5, and 10 μg/kg s.c.) significantly inhibited the Ro 60-0175- induced increases in plasma hormone levels. The data suggest that Ro 60-0175 increases hormone secretion by mechanisms independent of the activation of 5-HT_2C and/or 5-HT_2A receptors and suggest that Ro 60-0175 is not a highly selective 5-HT_2C receptor agonist.