In vivo Schild regression analyses using nonselective 5-HT_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_2C receptor antagonists using the Schild regression analysis in vivo. Objectives: To evaluate the behavioral effects of 5-HT_2C receptor agonists and antagonists, a series of nonselective 5-HT_2C receptor antagonists, the 5-HT _2A/2C receptor antagonist ketanserin, the 5-HT_2B receptor antagonist SB 204,741, the 5-HT_2B/2C receptor antagonist SB 200,646, and the peripherally acting 5-HT_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_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 pA₂ 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 _2A, 5-HT_2B, or peripheral 5-HT_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_2C receptor playing a prominent but not exclusive role.