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

Psychopharmacology (Berl). 2007 Aug;193(2):187-97. doi: 10.1007/s00213-007-0769-0. Epub 2007 Apr 1.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Conditioning, Operant / drug effects*
  • Dose-Response Relationship, Drug
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Regression Analysis
  • Reinforcement Schedule
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists*
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology


  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • Serotonin Receptor Agonists