Psychopharmacology

, Volume 178, Issue 2–3, pp 241–249

Agonist diversity in 5-HT2C receptor-mediated weight control in rats

  • Aska Hayashi
  • Masanori Suzuki
  • Masao Sasamata
  • Keiji Miyata
Original Investigation

Abstract

Rationale

Food intake and energy expenditure are the two main determinants of body weight. Given that 5-HT2C receptor agonists are reported to have effects on both energy expenditure and food intake, this strongly suggests that 5-HT2C receptor agonists have excellent potential for development as antiobesitiy drugs. One important issue in antiobesity drug development is whether the effects of the compound are maintained during chronic drug treatment.

Objectives

The purpose of the present study was to investigate the effect of repeated oral administration of three 5-HT2C receptor agonists, m-chlorophenylpiperazine (mCPP), d(S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (RO60-0175) and (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), on food intake and energy expenditure in rats.

Results

In the food intake study, mCPP, RO60-0175 and YM348 decreased food intake in a dose-dependent manner on day 1 of administration. On day 14 of repeated administration, the hypophagic effect of YM348 was lost and that of mCPP was reduced. In contrast, the hypophagic effect of RO60-0175 was maintained even after repeated administration. The hypophagic effects of all agonists were significantly inhibited by a 5-HT2C receptor antagonist, SB242084. In contrast to the hypophagic effects, no drug tolerance developed with respect to the hyperthermic effects of mCPP, RO60-0175, and YM348. The hyperthermic effects of these drugs were also inhibited by SB242084.

Conclusions

Together, the difference between compounds in their hypophagic effects and the similarity in their hyperthermic effects suggest a diversity in agonists in 5-HT2C receptor-mediated weight control in rats.

Keywords

(S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348) d(S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (RO60-0175) m-Chlorophenylpiperazine (mCPP) Food intake Body weight Body temperature 

References

  1. Akiyoshi J, Nishizono A, Yamada K, Nagayama H, Mifune K, Fujii I (1995) Rapid desensitization of serotonin 5-HT(2C) receptor-stimulated intracellular calcium mobilization in CHO cells transfected with cloned human 5-HT(2C) receptors. J Neurochem 64(6):2473–2479PubMedGoogle Scholar
  2. Aulakh CS, Mazzola-Pomietto P, Hill JL, Murphy DL (1994) Role of various 5-HT receptor subtypes in mediating neuroendocrine effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats. J Pharmacol Exp Ther 271(1):143–148PubMedGoogle Scholar
  3. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38(8):1083–1152CrossRefPubMedGoogle Scholar
  4. Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP (1998) Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54(1):94–104PubMedGoogle Scholar
  5. Boess FG, Martin IL (1994) Molecular biology of 5-HT receptors. Neuropharmacology 33(3–4):275–317CrossRefPubMedGoogle Scholar
  6. Briddon SJ, Leslie RA, Elliott JM (1998) Comparative desensitization of the human 5-HT2A and 5-HT2C receptors expressed in the human neuroblastoma cell line SH-SY5Y. Br J Pharmacol 125(4):727–734PubMedGoogle Scholar
  7. Clarke WP, Bond RA (1998) The elusive nature of intrinsic efficacy. Trends Pharmacol Sci 19(7):270–276CrossRefPubMedGoogle Scholar
  8. Clifton PG, Lee MD, Dourish CT (2000) Similarities in the action of Ro 60-0175, a 5-HT(2c) receptor agonist, and d-fenfluramine on feeding patterns in the rat. Psychopharmacologia 152(3):256–267CrossRefGoogle Scholar
  9. Collins S, Daniel KW, Rohlfs EM, Ramkumar V, Taylor IL, Gettys TW (1994) Impaired expression and functional activity of the beta 3- and beta 1-adrenergic receptors in adipose tissue of congenitally obese (C57BL/6J ob/ob) mice. Mol Endocrinol 8(4):518–527CrossRefPubMedGoogle Scholar
  10. Collins S, Daniel KW, Rohlfs EM (1999) Depressed expression of adipocyte beta-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents. Int J Obes Related Metab Disorders, J Int Assoc Study Obes 23(7):669–677Google Scholar
  11. Evans BA, Papaioannou M, Anastasopoulos F, Summers RJ (1998) Differential regulation of beta3-adrenoceptors in gut and adipose tissue of genetically obese (ob/ob) C57BL/6J-mice. Br J Pharmacol 124(4):763–771PubMedGoogle Scholar
  12. Fone KCF, Austin RH, Topham IA, Kennett GA, Punhani T (1998) Effect of chronic m-CPP on locomotion, hypophagia, plasma corticosterone and 5-HT(2C) receptor levels in the rat. Br J Pharmacol 123(8):1707–1715PubMedGoogle Scholar
  13. Fujioka K, Seaton TB, Rowe E, Jelinek CA, Raskin P, Lebovitz HE, Weinstein SP (2000) Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus. Diabetes Obes Metab 2(3):175–187CrossRefPubMedGoogle Scholar
  14. Grossman SP, Grossman L (1982) Iontophoretic injections of kainic acid into the rat lateral hypothalamus: effects on ingestive behavior. Physiol Behav 29(3):553–559CrossRefPubMedGoogle Scholar
  15. Grottick AJ, Corrigall WA, Higgins GA (2001) Activation of 5-HT2C receptors reduces the locomotor and rewarding effects of nicotine. Psychopharmacology 157(3):292–298CrossRefPubMedGoogle Scholar
  16. Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB (1997) Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem 272(28):17686–17693CrossRefPubMedGoogle Scholar
  17. Hayashi A, Sonoda R, Kimura Y, Takasu T, Suzuki M, Sasamata M, Miyata K (2004) Antiobesity effect of YM348, a novel 5-HT2C receptor agonist, in Zucker rats. Brain Res 1011(2):221–227CrossRefPubMedGoogle Scholar
  18. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, Lee CE, Cone RD, Elmquist JK (2002) Activation of central melanocortin pathways by fenfluramine. Science 297(5581):609–611CrossRefPubMedGoogle Scholar
  19. Kasser TR, Harris RBS, Martin RJ (1989) Level of satiety: in vitro energy metabolism in brain during hypophagic and hyperphagic body weight recovery. Am J Physiol Regul Integr Comp Physiol 257(6):26/6Google Scholar
  20. Kenakin T (1995) Agonist-receptor efficacy II: Agonist trafficking of receptor signals. Trends Pharmacol Sci 16(7):232–238CrossRefPubMedGoogle Scholar
  21. Kennett GA, Curzon G (1988a) Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 94(1):137–147PubMedGoogle Scholar
  22. Kennett GA, Curzon G (1988b) Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU 24969 only requires 5-HT1B receptors. Psychopharmacologia 96(1):93–100Google Scholar
  23. Kennett GA, Ainsworth K, Trail B, Blackburn TP (1997) BW 723C86, a 5-HT(2B) receptor agonist, causes hyperphagia and reduced grooming in rats. Neuropharmacology 36(2):233–239CrossRefPubMedGoogle Scholar
  24. Kennett G, Lightowler S, Trail B, Bright F, Bromidge S (2000) Effects of RO60-0175, a 5-HT(2C) receptor agonist, in three animal models of anxiety. Eur J Pharmacol 387(2):197–204CrossRefPubMedGoogle Scholar
  25. Kimura Y, Hatanaka K, Naito Y, Maeno K, Koakutsu A, Wanibuchi F, Yamaguchi T (2003) Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist. Eur J Pharmacol 483:37–43CrossRefGoogle Scholar
  26. Leung WYS, Thomas GN, Chan JCN, Tomlinson B (2003) Weight management and current options in pharmacotherapy: orlistat and sibutramine. Clin Ther 25(1):58–80CrossRefPubMedGoogle Scholar
  27. Martin GR, Humphrey PPA (1994) Receptors for 5-hydroxytryptamine: current perspectives on classification and nomenclature. Neuropharmacology 33(3–4):261–273CrossRefPubMedGoogle Scholar
  28. Martin JR, Bos M, Jenck F, Moreau J-L, Mutel V, Sleight AJ, Wichmann J, Andrews JS, Berendsen HHG, Broekkamp CLE, Ruigt GSF, Kohler C, Van Delft AML (1998) 5-HT(2C) receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286(2):913–924PubMedGoogle Scholar
  29. Mazzola-Pomietto P, Aulakh CS, Wozniak KM, Murphy DL (1996) Evidence that m-chlorophenylpiperazine-induced hyperthermia in rats is mediated by stimulation of 5-HT2C receptors. Psychopharmacologia 123(4):333–339Google Scholar
  30. McMahon FG, Fujioka K, Singh BN, Mendel CM, Rowe E, Rolston K, Johnson F, Mooradian AD (2000) Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch Int Med 160(14):2185–2191CrossRefGoogle Scholar
  31. Mystkowski P, Seeley RJ, Hahn TM, Baskin DG, Havel PJ, Matsumoto AM, Wilkinson CW, Peacock-Kinzig K, Blake KA, Schwartz MW (2000) Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss. J Neurosci 20(22):8637–8642Google Scholar
  32. Nonogaki K, Memon RA, Grunfeld C, Feingold KR, Tecott LH (2002) Altered gene expressions involved in energy expenditure in 5-HT(2C) receptor mutant mice. Biochem Biophy Res Commun 295(2):249–254CrossRefGoogle Scholar
  33. Porter RHP, Malcolm CS, Allen NH, Lamb H, Revell DF, Sheardown MJ (2001) Agonist-induced functional desensitization of recombinant human 5-HT2 receptors expressed in CHO-K1 cells. Biochem Pharmacol 62(4):431–438CrossRefPubMedGoogle Scholar
  34. Schreiber R, Selbach K, Asmussen M, Hesse D, De Vry J (2000) Effects of serotonin(1/2) receptor agonists on dark-phase food and water intake in rats. Pharmacol Biochem Behav 67(2):291–305CrossRefPubMedGoogle Scholar
  35. Shiraishi T, Simpson A (1982) Lateral hypothalamus neuron responses to electroosmotic 2-deoxy-d-glucose. Brain Res Bull 8(6):645–651CrossRefPubMedGoogle Scholar
  36. Stout BD, Clarke WP, Berg KA (2002) Rapid desensitization of the serotonin(2C) receptor system: effector pathway and agonist dependence. J Pharmacol Exp Ther 302(3):957–962CrossRefPubMedGoogle Scholar
  37. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT(2C) serotonin receptors. Nature 374(6522):542–546CrossRefPubMedGoogle Scholar
  38. Tuomisto JT, Pohjanvirta R, Unkila M, Tuomisto J (1995) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced anorexia and wasting syndrome in rats: aggravation after ventromedial hypothalamic lesion. Eur J Pharmacol Environ Toxicol Pharmacol Sect 293(4):309–317CrossRefGoogle Scholar
  39. Vickers SP, Benwell KR, Porter RH, Bickerdike MJ, Kennett GA, Dourish CT (2000) Comparative effects of continuous infusion of mCPP, Ro60-0175 and d-fenfluramine on food intake, water intake, body weight and locomotor activity in rats. Br J Pharmacol 130(6):1305–1314PubMedGoogle Scholar
  40. Vickers SP, Dourish CT, Kennett GA (2001) Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology 41(2):200–209CrossRefPubMedGoogle Scholar
  41. Vickers SP, Easton N, Webster LJ, Wyatt A, Bickerdike MJ, Dourish CT, Kennett GA (2003) Oral administration of the 5-HT2C receptor agonist, mCPP, reduces body weight gain in rats over 28 days as a result of maintained hypophagia. Psychopharmacology 167(3):274–280PubMedGoogle Scholar
  42. Wozniak KM, Aulakh CS, Hill JL, Murphy DL (1988) The effect of 8-OH-DPAT on temperature in the rat and its modification by chronic antidepressant treatments. Pharmacol Biochem Behav 30(2):451–456CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Aska Hayashi
    • 1
  • Masanori Suzuki
    • 1
  • Masao Sasamata
    • 1
  • Keiji Miyata
    • 1
  1. 1.Institute for Drug Discovery ResearchYamanouchi Pharmaceutical Co., LtdIbarakiJapan

Personalised recommendations