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 RS102,221 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 pA(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 RS102,221 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.