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In vivo Schild regression analyses using nonselective 5-HT2C receptor antagonists in a rat operant behavioral assay

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Abstract

Rationale

Although competitive antagonism experiments are critical tools in the classification of potential pharmacotherapies, no studies have quantitatively compared the potencies of 5-HT2C receptor antagonists using the Schild regression analysis in vivo.

Objectives

To evaluate the behavioral effects of 5-HT2C receptor agonists and antagonists, a series of nonselective 5-HT2C receptor antagonists, the 5-HT2A/2C receptor antagonist ketanserin, the 5-HT2B receptor antagonist SB 204,741, the 5-HT2B/2C receptor antagonist SB 200,646, and the peripherally acting 5-HT2C 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-HT2B 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-HT2A, 5-HT2B, or peripheral 5-HT2C 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-HT2C receptor playing a prominent but not exclusive role.

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Acknowledgment

The authors wish to thank Richard W. Hass, Amy Falcone, and Amy Schneider for their technical assistance. All experiments reported in this manuscript comply with the current laws and research regulations of the State of Pennsylvania and the USA.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA, 19140, USA

    Ellen A. Walker, Edward K. Brown Jr. & Steven N. Sterious

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  1. Ellen A. Walker
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  2. Edward K. Brown Jr.
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  3. Steven N. Sterious
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Correspondence to Ellen A. Walker.

Additional information

This research was supported by the National Institute on Drug Abuse Grant DA14673.

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Walker, E.A., Brown, E.K. & Sterious, S.N. In vivo Schild regression analyses using nonselective 5-HT2C receptor antagonists in a rat operant behavioral assay. Psychopharmacology 193, 187–197 (2007). https://doi.org/10.1007/s00213-007-0769-0

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