, Volume 114, Issue 1, pp 90–96 | Cite as

Evidence that 5-HT2C receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety

  • G. A. Kennett
  • K. Pittaway
  • T. P. Blackburn
Original Investigations


Four non-selective 5-HT2C/5-HT2A receptor antagonists, mianserin (2–8 mg/kg), 1-naphthyl piperazine (1-NP) (0.5–1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT2A receptor antagonists ketanserin (0.2–1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT1A, 5-HT1B andβ-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT1D receptor partial agonist andα2 adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H1 receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT2C/5-HT2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT2C/5-HT2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT2C receptor, although the possibility of 5-HT2B receptor mediation is discussed.

Key words

5-HT1C receptors 5-HT2 receptors 5-HT2B receptors 5-HT Anxiety Geller-Seifter test 


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  1. Alexander BS, Wood MD (1987) Stereoselective blockade of central (3-H) 5-hydroxytryptamine binding to multiple sites (5-HT1A, 5-HT1B and 5-HT1C) by mianserin and propranolol. J Pharm Pharmacol 39:664–666Google Scholar
  2. Baez M, Yu L, Cohen ML (1990) Pharmacological and molecular evidence that the contractile response to serotonin in rat stomach fundus is not mediated by the 5-hydroxytrptamine1C receptor. Mol Pharmacol 38:31–37Google Scholar
  3. Becker HC (1986) Comparison of the effects of the benzodiazepine midazolam and three serotonin antagonists on a consummatory conflict paradigm. Pharmacol Biochem Behav 24:1057–1064Google Scholar
  4. Blackburn TP, Thornber CW, Pearce RJ, Cox B (1988) In vitro studies with ICI 169,369, a novel 5-HT antagonist. Eur J Pharmacol 150:247–256Google Scholar
  5. Bressa GM, Marini S, Gregori S (1987) Serotonin S2 receptor blockade and generalised anxiety disorder. A double-blind study on ritanserin and lorazepam. Int J Clin Pharm Res VII:111–119Google Scholar
  6. Brocco, MJ, Koek W, Degryse A-D, Colpaert FC (1990) Comparative studies on the antipunishment effects of chlordiazepoxide, buspirone and ritanserin in the pigeon Geller-Seifter and Vogel conflict procedures. Behav Pharmacol 1:403–418Google Scholar
  7. Ceulemans DLS, Hoppenbrouwers MLJA, Gelders YG, Reyntjens AJM (1985) The influence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind placebo-controlled study versus lorazepam. Pharmacopsychiatry 18:303–305Google Scholar
  8. Clineschmidt BV, Flataker LM, Faison E, Holmes R (1979) An in vivo model for investigatingα 1 andα 2-receptors in the CNS: studies with mianserin. Arch Int Pharmacodyn 242:59–76Google Scholar
  9. Clineschmidt BV, Reiss DR, Pettibone DJ, Robinson JL (1985) Characterization of 5-hydroxytryptamine receptors in rat stomach fundus. J Pharmacol Exp Ther 235:696–708Google Scholar
  10. Cohen ML, Fuller RW, Kurz KD (1983) LY 53857, a selective and potent serotonergic (5-HT2) receptor antagonist, does not lower blood pressure in the spontaneous hypertensive rat. J Pharmacol Exp Ther 227:327–332Google Scholar
  11. Colpaert FC, Meert TF, Niemegeers CJE, Janssen PAJ (1985) Behavioural and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in the rat. Psychopharmacology 86:45–54Google Scholar
  12. Conn PJ, Sanders-Bush E (1987) Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT2 and 5-HT1C) receptors. J Pharmacol Exp Ther 242:552–557Google Scholar
  13. Conti L, Pinder RM (1979) A controlled comparative trial of mianserin and diazepam in the treatment of anxiety states in psychiatric outpatients. J Int Med Res 7:285–289Google Scholar
  14. Cook L, Sepinwall J (1975) Behavioural analysis of the effects and mechanisms of action of benzodiazepines. In: Costa E, Greengard P (eds) Mechanisms of action of benzodiazepines. Raven, New York, pp 1–28Google Scholar
  15. Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ (1988) Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol 40:302–305Google Scholar
  16. Deacon R, Gardner CF (1986) Benzodiazepine and 5-HT ligands in a rat conflict test. Br J Pharmacol 88:330PGoogle Scholar
  17. Dourish CT, Clark ML, Fletcher A, Iversen SD (1989) Evidence that blockade of postsynaptic 5-HT1 receptors elicits feeding in satiated rats. Psychopharmacology 97:54–58Google Scholar
  18. File SE, Johnston AL (1989) Lack of effect of 5-HT3 receptor antagonists in the social interaction and elevated plus-maze tests of anxiety in the rat. Psychopharmacology 99:248–251Google Scholar
  19. Fletcher PJ (1988) Increased food intake in satiated rats induced by 5-HT antagonists methysergide, metergoline and ritanserin. Psychopharmacology 96:237–242Google Scholar
  20. Foquet M, Hoyer D, Pardo LA, Parekh A, Kluxen FW, Kalkman HO, Stuhmer W, Lubber H (1992a) Cloning and functional characterization of the rat stomach fundus serotonin receptor. EMBO J 11:3481–3487Google Scholar
  21. Foquet M, Nguyen H, Le H, Lubbert H (1992b) Structure of the mouse 5-HT1C, 5-HT2 and stomach fundus serotonin receptor genes. Neuroreport 3:345–348Google Scholar
  22. Gadie B, Lane AC, McCarthy PS, Tulloch IF, Walter DS (1983) 2-Alkyl analogues of RX 781094: potent selective antagonists at centralα 2-adrenoceptors. Br J Pharmacol 78:312PGoogle Scholar
  23. Gleeson S, Ahlers ST, Mansbach RS, Foust JM, Barrett JE (1989) Behavioural studies with anxiolytic drugs. VI: Effects on punished responding of drugs interacting with serotonin receptor subtypes. J Pharmacol Exp Ther 250:809–817Google Scholar
  24. Glennon RA, EI-Kader A, Ismaiel M, McCarthy BG, Peroutka SJ (1989) Binding of arylpiperazines to 5-HT3 serotonin receptors: results of a structure-affinity study. Eur J Pharmacol 168:387–392Google Scholar
  25. Graeff FG (1974) Tryptamine antagonists and punished behaviour. J Pharmacol Exp Ther 189:344–350Google Scholar
  26. Graeff FG, Zuarde AW, Giglio JS, Lima Filho EC, Karniol IG (1985) Effect of metergoline on human anxiety. Psychopharmacology 86:334–338Google Scholar
  27. Hartig PR, Branchek TA, Weinshank RL (1992) A subfamily of 5-HT1D receptor genes. TIPS 13:152–159Google Scholar
  28. Hill SJ, Young JM, Marrian DH (1977) Specific binding of [3H]-mepyramine to histamine H1 receptors in intestinal smooth muscle. Nature 270:361–363Google Scholar
  29. Hoffman B, Mezey E (1989) Distribution of serotonin 5-HT1C receptor mRNA in adult rat brain. FEBS Lett 247:453–462Google Scholar
  30. Hoyer D (1989) 5-hydroxytryptamine receptors and effector coupling mechanisms in peripheral tissues. In: Fozard J (ed) Peripheral actions of 5-HT. Oxford University Press, Oxford, pp 72–99Google Scholar
  31. Hoyer D (1990) Competitive antagonism by recognised 5-HT2 receptor antagonists at 5-HT1C receptors. Naunyn-Schmiedebergs Arch Pharmacol 341:Suppl. R88Google Scholar
  32. Kahn RS, Van Praag HM, Wetzler S, Asnis GM, Barr G (1988) Serotonin and anxiety revisited. Biol Psychiatry 23:189–208Google Scholar
  33. Kalus O, Kahn RS, Wetzler S, Asnis GM, Van Praag HM (1990) Hypersensitivity tom-chlorophenyl piperazine in a subject with subclinical panic attacks. Biol Psychiatry 28:1053–1057Google Scholar
  34. Kennett GA (1992) 5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction test. Psychopharmacology 107:397–402Google Scholar
  35. Kennett GA, Curzon G (1988a) Evidence that mCPP may have behavioural effects mediated by 5-HT1C receptors. Br J Pharmacol 94:137–147Google Scholar
  36. 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. Psychopharmacology 96:93–100Google Scholar
  37. Kennett GA, Curzon G (1991) Potencies of antagonists indicate that 5-HT1C receptors mediate 1–3 (chlorophenyl) piperazine-induced hypophagia. Br J Pharmacol 103:2016–2020Google Scholar
  38. Kennett GA, Dourish CT, Curzon G (1987) 5-HT1B agonists induce anorexia at a postsynaptic site. Eur J Pharmacol 141:137–147Google Scholar
  39. Kennett GA, Whitton P, Shah K, Curzon G (1989) Anxiogenic-like effects ofmCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Eur J Pharmacol 164:445–454Google Scholar
  40. Khan MC, Bennie EH, Stulemeijer SM, Ravens MA (1983) Mianserin and doxepin in the treatment of outpatient depression with anxiety. Br J Clin Pharmacol 15:213S-218SGoogle Scholar
  41. Koek W, Jackson A, Colpaert FC (1992) Behavioural pharmacology of antagonists at 5-HT2/5-HT1C receptors. Neurosci Biobehav Rev 16:95–105Google Scholar
  42. Leone CML, De Aguir JC, Graeff FG (1983) Role of 5-hydroxytryptamine in amphetamine effects on punished and unpunished behaviour. Psychopharmacology 80:78–82Google Scholar
  43. Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PAJ (1981) Receptor binding profile of R41 468, a novel antagonist of 5-HT2 receptors. Life Sci 28:1015–1022Google Scholar
  44. Mason P, Skinner J, Lusting D (1987) Two tests in rats for antianxiety effect of clinical anxiety attenuating antidepressants. Psychopharmacology 92:30–34Google Scholar
  45. Moser PC (1989) An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone. Psychopharmacology 99:48–53Google Scholar
  46. Murphy JE (1978) Mianserin in the treatment of depressive illness and anxiety states in general practice. Br J Clin Pharmacol 5:81S-85SGoogle Scholar
  47. Nelson DR, Thomas DR (1989) (3-H)-BRL 43694 (Granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes. Biochem Pharmacol 10:1693–1695Google Scholar
  48. Pangalila-Ratu Langi EA, Janssen PAJ (1988) Ritanserin in the treatment of generalised anxiety disorders: a placebo-controlled trial. Hum Psychopharmacol 3:207–212Google Scholar
  49. Piggott TA, Zohar J, Hill JL, Bernstein SE, Grover GN, Zohar-Kadouch RC, Murphy DL (1991) Metergoline blocks the behavioural and neuroendocrine effects of oralmCPP in obsessive-compulsive disorder. Biol Psychiatry 29:418–426Google Scholar
  50. Piper D, Upton N, Thomas DL, Nicholass J (1988) The effects of 5-HT3 receptor antagonists BRL 43694 and GR 38032F in animal models of anxiety. Br J Pharmacol 94:314PGoogle Scholar
  51. Russell GFM, Niaz U, Wakeling A, Slade PD (1978) Comparative double-blind trial of mianserin hydrochloride (Organon GB94) and diazepam in patients with depressive illness. Br J Pharmacol 5:57S-65SGoogle Scholar
  52. Schoeffter P, Hoyer D (1989a) Interaction of arylpiperazines with 5-HTA, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist? Naunyn-Schmiedebergs Arch Pharmacol 339:675–682Google Scholar
  53. Schoeffter P, Hoyer D (1989b) 5-Hydroxytryptamine 5-HT1B and 5-HT1D receptors meditating inhibition of adenylate cyclase activity. Pharmacological comparison with special reference to the effects of yohimbine, rauwolscine and someβ-adrenoceptor antagonists. Naunyn-Schmiedebergs Arch Pharmacol 340:285–292Google Scholar
  54. Seibyl JP, Krystal JH, Price LH, Woods SW, D'Amico CD, Henninger GR, Charney DS (1989) Effects of ritanserin on the behavioural, neuroendocrine and cardiovascular responses to meta chlorophenylpiperazine in healthy subjects. Psychiat Res 38:227–236Google Scholar
  55. Sepinwall J, Cook L (1980) Mechanism of action of the benzodiazepines: Behavioural aspects. Fed Proc 39:3024–3031Google Scholar
  56. Stefanski R, Palejko W, Kostowski W, Plaznik A (1992) The comparison of benzodiazepine derivatives and serotonergic agonists and antagonists in two animal models of anxiety. Neuropharmacology 31:1251–1258Google Scholar
  57. Stein L, Wise CD, Belluzzi JD (1975) Effects of benzodiazepines on central serotonergic mechanisms. In: Costa E, Greengard P (eds) Mechanism of action of benzodiazepines. Raven, New York, pp 29–44Google Scholar
  58. Tyers MB, Costall B, Domeney A, Jones BJ, Kelly ME, Naylor RJ, Oakley NR (1987) The anxiolytic activities of 5-HT3 antagonists in laboratory animals. Neurosci Lett 29 (suppl): S6Google Scholar
  59. Westenberg HGM, Den Boer JA (1989) Serotonin-influencing drugs in the treatment of panic disorder. Psychopathology 22 (suppl 1): 68–77Google Scholar
  60. Whitton P, Curzon G (1990) Anxiogenic-like effect of infusing 1-(3-chlorophenyl) piperazine (mCPP) into the hippocampus. Psychopharmacology 100:138–140Google Scholar
  61. Winter JD (1972) Comparison of chlordiazepoxide, methysergide and cinanserin as modifiers of punished behaviour and as antagonists ofN, N-dimethyltryptamine. Arch Int Pharmacodyn Ther 197:147–159Google Scholar
  62. Zohar J, Insel TR (1987) Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment and pathophysiology. Biol Psychiatry 22:667–687Google Scholar
  63. Zohar J, Mueller EA, Insel TR, Zohar-Kadouch RC, Murphy DL (1987) Serotonergic responsivity in obsessive compulsive disorder. Comparison of patients and healthy controls. Arch Gen Psychiatry 45:167–172Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • G. A. Kennett
    • 1
  • K. Pittaway
    • 1
  • T. P. Blackburn
    • 1
  1. 1.SmithKline Beecham PharmaceuticalsHarlowUK

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