Vol. 304, Issue 3, 1209-1216, March 2003

Neuroendocrine Evidence That (S)-2-(Chloro-5-fluoro-indol- l-yl)-1-methylethylamine Fumarate (Ro 60-0175) Is Not a Selective 5-Hydroxytryptamine_2C Receptor Agonist

K. J. Damjanoska, N. A. Muma, Y. Zhang, D. N. D'Souza, F. Garcia, G. A. Carrasco, G. H. Kindel, K. A. Haskins, M. Shankaran, B. R. Petersen and L. D. Van De Kar

Department of Pharmacology and Experimental Therapeutics and Center for Serotonin Disorders Research, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois

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-l-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.