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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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References

  • Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol Chemother 14:48–58

    PubMed  CAS  Google Scholar 

  • Baxter GS (1996) Novel discriminatory ligands for 5-HT2B receptors. Behav Brain Res 73:149–152

    PubMed  CAS  Google Scholar 

  • Bonhaus DW, Bach C, DeSouza A, Salazar FH, Matsuoka BD, Zuppan P, Chan HW, Eglen RM (1995) The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol 115:622–628

    PubMed  CAS  Google Scholar 

  • Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM (1997) RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 36:621–629

    Article  PubMed  CAS  Google Scholar 

  • Brady LS, Barrett JE (1985) Effects of serotonin receptor antagonists on punished responding maintained by stimulus-shock termination or food presentation in squirrel monkeys. J Pharmacol Exp Ther 234:106–112

    PubMed  CAS  Google Scholar 

  • Burris KD, Sanders-Bush E (1992) Unsurmountable antagonism of brain 5-hydroxytryptamine2 receptors by (+)-lysergic acid diethylamide and bromo-lysergic acid diethylamide. Mol Pharmacol 42:826–830

    PubMed  CAS  Google Scholar 

  • Callahan PM, Cunningham KA (1995) Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors. J Pharmacol Exp Ther 274:1414–1424

    PubMed  CAS  Google Scholar 

  • Conn PJ, Sanders-Bush E (1987) Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT-2 and 5-HT-1c) receptors. J Pharmacol Exp Ther 242:552–557

    PubMed  CAS  Google Scholar 

  • Cunningham KA, Callahan PM, Appel JB (1986) Discriminative stimulus properties of the serotonin agonist MK212. Psychopharmacology (Berl) 90:193–197

    CAS  Google Scholar 

  • Cussac D, Newman-Tancredi A, Quentric Y, Carpentier N, Poissonnet G, Parmentier JG, Goldstein S, Millan MJ (2002) Characterization of phospholipase C activity at h5-HT2C compared with h5-HT2B receptors: influence of novel ligands upon membrane-bound levels of [3H]phosphatidylinositols. Naunyn Schmiedebergs Arch Pharmacol 365:242–252

    Article  PubMed  CAS  Google Scholar 

  • De Vry J, Schreiber R, Daschke A, Jentzsch KR (2003) Effects of serotonin 5-HT(1/2) receptor agonists in a limited-access operant food intake paradigm in the rat. Eur Neuropsychopharmacol 13:337–345

    Article  PubMed  CAS  Google Scholar 

  • Dekeyne A, Girardon S, Millan MJ (1999) Discriminative stimulus properties of the novel serotonin (5-HT)2C receptor agonist, RO 60-0175: a pharmacological analysis. Neuropharmacology 38:415–423

    Article  PubMed  CAS  Google Scholar 

  • Fiorella D, Rabin RA, Winter JC (1995a) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I. Antagonist correlation analysis. Psychopharmacology (Berl) 121:347–356

    Article  CAS  Google Scholar 

  • Fiorella D, Rabin RA, Winter JC (1995b) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of m-chlorophenylpiperazine. Psychopharmacology (Berl) 119:222–230

    Article  CAS  Google Scholar 

  • Forbes IT, Kennett GA, Gadre A, Ham P, Hayward CJ, Martin RT, Thompson M, Wood MD, Baxter GS, Glen A et al (1993) N-(1-methyl-5-indolyl)-N’-(3-pyridyl)urea hydrochloride: the first selective 5-HT1C receptor antagonist. J Med Chem 36:1104–1107

    Article  PubMed  CAS  Google Scholar 

  • Gleeson S, Ahlers ST, Mansbach RS, Foust JM, Barrett JE (1989) Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes. J Pharmacol Exp Ther 250:809–817

    PubMed  CAS  Google Scholar 

  • Gommans J, Hijzen TH, Maes RA, Olivier B (1998) Discriminative stimulus effects of mCPP: Evidence for a 5-HT2C receptor mode of action. Psychopharmacology (Berl) 137:292–302

    Article  CAS  Google Scholar 

  • Hamik A, Peroutka SJ (1989) 1-(m-chlorophenyl)piperazine (mCPP) interactions with neurotransmitter receptors in the human brain. Biol Psychiatry 25:569–575

    Article  PubMed  CAS  Google Scholar 

  • Hoyer D (1988a) Functional correlates of serotonin 5-HT1 recognition sites. J Recept Res 8:59–81

    PubMed  CAS  Google Scholar 

  • Hoyer D (1988b) Molecular pharmacology and biology of 5-HT1C receptors. Trends Pharmacol Sci 9:89–94

    Article  PubMed  CAS  Google Scholar 

  • Kennett GA, Curzon G (1988) Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 94:137–147

    PubMed  CAS  Google Scholar 

  • Kennett GA, Pittaway K, Blackburn TP (1994a) Evidence that 5-HT2c receptor antagonists are anxiolytic in the rat Geller–Seifter model of anxiety. Psychopharmacology (Berl) 114:90–96

    Article  CAS  Google Scholar 

  • Kennett GA, Wood MD, Glen A, Grewal S, Forbes I, Gadre A, Blackburn TP (1994b) In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. Br J Pharmacol 111:797–802

    PubMed  CAS  Google Scholar 

  • Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P, Blackburn TP (1996) In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties. Br J Pharmacol 117:427–434

    PubMed  CAS  Google Scholar 

  • Labrecque J, Fargin A, Bouvier M, Chidiac P, Dennis M (1995) Serotonergic antagonists differentially inhibit spontaneous activity and decrease ligand binding capacity of the rat 5-hydroxytryptamine type 2C receptor in Sf9 cells. Mol Pharmacol 48:150–159

    PubMed  CAS  Google Scholar 

  • Mansbach RS, Barrett JE (1986) Effects of MK-212 (6-chloro-2[1-piperazinyl]pyrazine) on schedule-controlled behavior and their reversal by 5-HT antagonists in the pigeon. Neuropharmacology 25:13–19

    Article  PubMed  CAS  Google Scholar 

  • McCreary AC, Filip M, Cunningham KA (2003) Discriminative stimulus properties of (+)-fenfluramine: the role of 5-HT2 receptor subtypes. Behav Neurosci 117:212–221

    Article  PubMed  CAS  Google Scholar 

  • McMillan DE, Katz JL (2002) Continuing implications of the early evidence against the drive-reduction hypothesis of the behavioral effects of drugs. Psychopharmacology (Berl) 163:251–264

    Article  CAS  Google Scholar 

  • Meert TF, Melis W, Aerts N, Clincke G (1997) Antagonism of meta-chlorophenylpiperazine-induced inhibition of exploratory activity in an emergence procedure, the open field test, in rats. Behav Pharmacol 8:353–363

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ (2005) Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapies 60:441–460

    Google Scholar 

  • Millan MJ, Peglion JL, Lavielle G, Perrin-Monneyron S (1997) 5-HT2C receptors mediate penile erections in rats: actions of novel and selective agonists and antagonists. Eur J Pharmacol 325:9–12

    Article  PubMed  CAS  Google Scholar 

  • Minnema DJ, Hendry JS, Rosecrans JA (1984) Discriminative stimulus properties of pizotifen maleate (BC105): a putative serotonin antagonist. Psychopharmacology (Berl) 83:200–204

    Article  CAS  Google Scholar 

  • Peroutka SJ (1986) Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex. J Neurochem 47:529–540

    Article  PubMed  CAS  Google Scholar 

  • Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ (1999) Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 128:13–20

    Article  PubMed  CAS  Google Scholar 

  • Robertson DW, Bloomquist W, Wong DT, Cohen ML (1992) mCPP but not TFMPP is an antagonist at cardiac 5HT3 receptors. Life Sci 50:599–605

    Article  PubMed  CAS  Google Scholar 

  • Schlag BD, Lou Z, Fennell M, Dunlop J (2004) Ligand dependency of 5-hydroxytryptamine 2C receptor internalization. J Pharmacol Exp Ther 310:865–870

    Article  PubMed  CAS  Google Scholar 

  • Schoeffter P, Hoyer D (1989) Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist? Naunyn Schmiedebergs Arch Pharmacol 339:675–683

    Article  PubMed  CAS  Google Scholar 

  • Sterious SN, Walker EA (2003) Potency differences for d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 as an antagonist of peptide and alkaloid mu-agonists in an antinociception assay. J Pharmacol Exp Ther 304:301–309

    Article  PubMed  CAS  Google Scholar 

  • Takemori AE (1974) Determination of pharmacological constants: use of narcotic antagonists to characterize analgesic receptors. In: Braude M, Harris LS, May E, Smith JP, Villarreal J (eds) Narcotic antagonists. Raven, New York, pp 335–344

    Google Scholar 

  • Tallarida RJ, Raffa RB (1992) Receptor regulation, competitive antagonism and pA2. Life Sci 51:PL61–PL65

    Article  PubMed  CAS  Google Scholar 

  • Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ, Kennett GA (2001) Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists. Pharmacol Biochem Behav 69:643–652

    Article  PubMed  CAS  Google Scholar 

  • Walker EA, Kohut SJ, Hass RW, Brown EK Jr, Prabandham A, Lefever T (2005) Selective and nonselective serotonin antagonists block the aversive stimulus properties of MK212 and m-chlorophenylpiperazine (mCPP) in mice. Neuropharmacology 49:1210–1219

    Article  PubMed  CAS  Google Scholar 

  • Wenger GR (1980) Cumulative dose–response curves in behavioral pharmacology. Pharmacol Biochem Behav 13:647–651

    Article  PubMed  CAS  Google Scholar 

  • Wolff MC, Leander JD (2000) A comparison of the behavioural effects of 5-HT2A and 5-HT2C receptor agonists in the pigeon. Behav Pharmacol 11:355–364

    PubMed  CAS  Google Scholar 

Download references

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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