In vivo Schild regression analyses using nonselective 5-HT sub(2C) receptor antagonists in a rat operant behavioral assay

Rationale: Although competitive antagonism experiments are critical tools in the classification of potential pharmacotherapies, no studies have quantitatively compared the potencies of 5-HT sub(2C) receptor antagonists using the Schild regression analysis in vivo. Objectives: To evaluate the behavioral effects of 5-HT sub(2C) receptor agonists and antagonists, a series of nonselective 5-HT sub(2C) receptor antagonists, the 5-HT sub(2A/2C) receptor antagonist ketanserin, the 5-HT sub(2B) receptor antagonist SB 204,741, the 5-HT sub(2B/2C) receptor antagonist SB 200,646, and the peripherally acting 5-HT sub(2C) receptor antagonist RS102221 were evaluated for their capacity to competitively antagonize the agonists MK212, mCPP, or BW723C86 in rats. Materials and methods: Male Sprague-Dawley rats (N = 28) were trained to respond under a fixed ratio 10 schedule of food reinforcement. A multiple-trial, cumulative-dosing procedure was used to evaluate the capacity of the compounds to suppress response rates. Results: MK212, mCPP, and the 5-HT sub(2B) receptor agonist BW723C86 dose-dependently decreased response rates. Only metergoline, mianserin, and methysergide produced a dose-dependent antagonism of the rate-decreasing effects of both mCPP and MK212. Apparent pA sub(2) analysis indicated that metergoline, mianserin, and methysergide were approximately equipotent as antagonists overall. Metergoline and mianserin failed to block the rate-decreasing effects of BW723C86. Ketanserin, SB 200,646, SB 204,741, and RS102221 failed to block either mCPP or MK212, suggesting that 5-HT sub(2A), 5-HT sub(2B), or peripheral 5-HT sub(2C) receptors do not play a primary role in the rate-decreasing effects of these two agonists. Conclusions: Taken together, these antagonism profiles suggest that the agonists MK212 and mCPP produce their rate-decreasing effects through a combination of 5-HT receptors with the 5-HT sub(2C) receptor playing a prominent but not exclusive role.