, Volume 107, Issue 2–3, pp 379–384 | Cite as

5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model

  • G. A. Kennett
Original Investigations


The effects of a range of 5-HT receptor antagonists were examined in an animal model of anxiety — the social interaction test. Six antagonists with high affinity for 5-HT1C receptors; mianserin, (+) mianserin, 1-naphthyl piperazine, ICI 169 369, pizotifen and LY 53857 all increased the time spent in active social interaction by pairs of weight-matched rats under high light unfamiliar conditions. As locomotion was only increased by 1-NP and then only at high doses, the effect of the drugs is consistent with anxiolysis. These properties were shared by the benzodiazepine anxiolytic chlordiazepoxide but not by the specific 5-HT2 antagonists ketanserin and altanserin, nor by the 5-HT1A and 5-HT1B antagonists cyanopindolol and pindolol. Similarly, neither the adrenergic α2 antagonist idazoxan, the α2 antagonist and putative 5-HT1D partial agonist yohimbine nor the H1 antagonist mepyramine had any significant effect. Since (+)mianserin, LY 53857 and ICI 169 369 at least have low affinity for 5-HT3 receptors these receptors are also unlikely to be involved. The results therefore imply that the observed anxiolytic effects of the drugs are likely to be mediated by 5-HT1C receptor blockade.

Key words

Anxiety 5-HT 5-HT1C receptors Social interaction Mianserin Benzodiazepines Ketanserin 


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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 39:664–666PubMedGoogle Scholar
  2. 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
  3. Blackburn TP, Thornber CW, Pearce RJ, Cox B (1988) In vitro studies with ICI 169 369, a chemically novel 5-HT antagonist. Eur J Pharmacol 150:247–256CrossRefPubMedGoogle Scholar
  4. Caccia S, Ballabio M, Samanin R (1981) m-Chlorophenylpiperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J Pharm Pharmacol 34:477–478Google Scholar
  5. 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 18:303–305PubMedGoogle Scholar
  6. Charney DS, Woods SW, Goodman WK, Heninger GR (1987) Serotonin function in anxiety. II. Effects of the serotonin agonist mCPP in panic disorder patients and healthy patients. Psychopharmacology 92:14–21CrossRefPubMedGoogle Scholar
  7. Clineschmidt BV, Flataker LM, Faison E, Holmes R (1979) An in vivo model for investigating α1 and α2-receptors in the CNS: studies with mianserin. Arch Int Pharmacodyn 242:59–76PubMedGoogle Scholar
  8. 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 227:327–332PubMedGoogle Scholar
  9. 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 86:45–54CrossRefPubMedGoogle Scholar
  10. 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 242:552–557PubMedGoogle Scholar
  11. Conti L, Pinder RM (1979) A controlled comparative trial of mian-serin and diazepam in the treatment of anxiety states in psychiatric outpatients. J Int Med Res 7:285–289PubMedGoogle Scholar
  12. 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 Press, New York, pp 1–28Google Scholar
  13. Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ (1988) Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol 40:302–305PubMedGoogle Scholar
  14. Deacon R, Gardner CF (1986) Benzodiazepine and 5-HT ligands in a rat conflict test. Br J Pharmacol 88:330PGoogle Scholar
  15. File SE (1981) Behavioural effects of serotonin depletion. In: Clifford Rose E (ed) Metabolic disorders of the nervous system. Pitmans, London, pp 429–445Google Scholar
  16. File SE (1985) Animal models for predicting clinical efficacy of anxiolytic drugs: social behaviour. Neuropsychobiology 13:55–62PubMedGoogle Scholar
  17. Gadie B, Lane AC, McCarthy PS, Tulloch IF, Walter DS (1983) 2-Alkyl analogues of RX 781094: potent selctive antagonists at central α2-adrenoceptors. Br J Pharmacol 78:312PGoogle Scholar
  18. Gardner CR (1986) Recent developments in 5-HT-related pharmacology of of animal models of anxiety. Pharmacol Biochem Behav 24:1479–1485CrossRefPubMedGoogle Scholar
  19. 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 250:809–817PubMedGoogle Scholar
  20. Glennon RA, El-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 168:387–392CrossRefPubMedGoogle Scholar
  21. Graeff FG (1974) Tryptamine antagonists and punished behaviour. J Pharmacol Exp Ther 189:344–350PubMedGoogle Scholar
  22. Graeff FG, Zuarde AW, Giglio JS, Lima Filho EC, Karniol IG (1985) Effect of metergoline on human anxiety. Psychopharmacology 86:334–338Google Scholar
  23. Guy AP, Gardner CR (1985) Pharmacological characterization of a modified social interaction model of anxiety in the rat. Neuropsychobiology 13:194–201PubMedGoogle Scholar
  24. 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
  25. Hoyer D (1990) Competitive antagonism by recognised 5-HT2 receptor antagonists at 5-HT1C receptors. Naunyn Schmiedeberg's Arch Pharmacol 341:Suppl R88Google Scholar
  26. Hoyer D, Pazos A, Probst A, Palacios JM (1986) Serotonin receptors in the human brain. 1. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Res 376:85–96CrossRefPubMedGoogle Scholar
  27. Jones BJ, Costall B, Domeney AM, Kelly ME, Naylor RJ, Oakley NR, Tyers MB (1988) The potential anxiolytic activity of GR 38032F, a 5-HT3-receptor antagonist. Br J Pharmacol 93:985–993PubMedGoogle Scholar
  28. Kahn RS, Van Praag HM, Wetzler S, Asnis GM, Barr G (1988) Serotonin and anxiety revisited. Biol Psychiatry 23:189–208CrossRefPubMedGoogle Scholar
  29. Kahn RS, Wetzler S, Asnis GM, Kling MA, Suckow RF, Van Praag HM (1990) Effects of m-chlorophenylpiperazine in normal subjects: a dose-response study. Psychopharmacology 100:339–344Google Scholar
  30. Kennett GA, Curzon G (1988a) Evidence that mCPP may have behavioural effects mediated by 5-HT1C receptors. Br J Pharmacol 94:137–147PubMedGoogle Scholar
  31. Kennett GA, Curzon G (1988b) Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia by RU 24969 only requires 5-HT1B receptors. Psychopharmacology 96:93–100Google Scholar
  32. Kennett GA, Blackburn TP (1990) Anxiolytic-like actions of BRL 46470A — a novel 5-HT3 receptor antagonist. J Psychopharmacology 4:4Google Scholar
  33. Kennett GA, Curzon (1991) Potencies of antagonists indicate that 5-HT1C receptors mediate 1–3(chlorophenyl) piperazine-induced hypophagia. Br J Pharmacol 103:2016–2020PubMedGoogle Scholar
  34. Kennett GA, Dourish CT, Curzon G (1987) 5-HT1B agonists induce anorexia at a postsynaptic site. Eur J Pharmacol 141:137–147CrossRefGoogle Scholar
  35. Kennett GA, Whitton P, Shah K, Curzon G (1989) Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Eur J Pharmacol 164:445–454CrossRefPubMedGoogle Scholar
  36. Kennett GA, Whitton P, Curzon G (1990) ID50 values of antagonists vs mCPP-induced hypophagia and 5-HT2-mediated headshakes indicate that 5-HT1C sites mediate the hypophagia. Br J Pharmacol 99:241PGoogle Scholar
  37. 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-218SPubMedGoogle Scholar
  38. Kilpatrick GJ, Jones BJ, Tyers MB (1988) Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 330:746–749CrossRefGoogle Scholar
  39. 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
  40. 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 28:1015–1022CrossRefPubMedGoogle Scholar
  41. Martin LL, Sanders-Bush E (1982) Comparison of the pharmacological characteristics of 5-HT1 and 5-HT2 binding sites with those of serotonin autoreceptors which modulate serotonin release. Naunyn-Schmiedeberg's Arch Pharmacol 321:165–170CrossRefGoogle Scholar
  42. Mason P, Skinner J, Luttinger D (1987) Two tests in rats for antianxiety effect of clinically anxiety attenuating antidepressants. Psychopharmacology 92:30–33Google Scholar
  43. Mueller EA, Murphy DL, Sunderland T (1985) Neuroendocrine effects of m-chlorophenylpiperazine, a serotonin agonist in humans. J Clin Endocrinol Metab 61:1179–1184PubMedGoogle Scholar
  44. Murphy JE (1978) Mianserin in the treatment of depressive illness and anxiety states in general practice. Br J Clin Pharmacol 5:81S-85SPubMedGoogle Scholar
  45. 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 10:1693–1695CrossRefGoogle Scholar
  46. Nicholson VS, Wieringa JH, Van Delft AML (1982) Comparative pharmacology of mianserin, its main metabolites and 6-azamianserin. Naunyn-Schmiedeberg's Arch Pharmacol 319:48–55CrossRefGoogle Scholar
  47. Niesink RJM, Van Ree JM (1982) Antidepressant drugs normalise the increased social behaviour of pairs of male rats induced by short term isolation. Neuropharmacology 21:1343–1348CrossRefPubMedGoogle Scholar
  48. Pigott TA, Zohar J, Hill JL, Bernstein SE, Grover GN, Zohar-Kadouch RC, Murphy DL (1990) Metergoline blocks the behavioural and neuroendocrine effects of orally administered mCPP in obsessive-compulsive disorder. Biol Psychiatry 29:418–426CrossRefGoogle Scholar
  49. 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
  50. 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 Clin Pharmacol 5:57S-65SPubMedGoogle Scholar
  51. Schoeffter P, Hoyer D (1989a) Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist? Naunyn-Schmiedeberg's Arch Pharmacol 339:675–682CrossRefGoogle Scholar
  52. Schoeffter P, Hoyer D (1989b) 5-Hydroxytryptamine 5-HT1B and 5-HT1D receptors mediating inhibition of adenylate cyclase activity. Pharmacological comparison with special reference to the effects of yohimbine, rauwolscine and some β-adrenoceptor antagonists. Naunyn-Schmiedeberg's Arch Pharmacol 340:285–292Google Scholar
  53. Seibyl JP, Krystal JH, Price LH, Woods SW, Heninger GR, Charney DS (1989) 5-HT function in the biochemical and behavioural responses to mCPP in healthy subjects and schizophrenics. Am Soc Neurosci Abstr 15:485.21Google Scholar
  54. Sepinwall J, Cook L (1980) Mechanism of action of the benzodiazepines: Behavioral aspect. Fed Proc 39:3024–3031PubMedGoogle Scholar
  55. Sills MA, Wolfe BB, Frazer A (1984) Determination of selective and non-selective compounds for the 5-HT1A and 5-HT1B receptor subtypes in rat frontal cortex. J Pharmacol Exp Ther 231:480–487PubMedGoogle Scholar
  56. 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 Press, New York, pp 29–44Google Scholar
  57. Tricklebank MD, Forler C, Fozard J (1984) The involvement of subtypes of the 5-HT1A receptor and of catecholaminergic systems in the behavioural response to 8-Hydroxy-2-(di-n-propylamino)tetralin in the rat. Eur J Pharmacol 106:271–277CrossRefPubMedGoogle Scholar
  58. Whitton P, Curzon G (1990) Anxiogenic-like effect of infusing 1-(3-chlorophenyl)piperazine (mCPP) into the hippocampus. Psychopharmacology 100:138–140Google Scholar
  59. Winter JD (1972) Comparison of chlordiazepoxide, methysergide and cinanserin as modifiers of punished behaviour and as antagonists of N,N-dimethyltryptamine. Arch Int Pharmacodyn Ther 197:147–159PubMedGoogle Scholar
  60. Zohar J, Insel TR (1987) Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment and pathophysiology. Biol Psychiatry 22:667–687CrossRefPubMedGoogle Scholar
  61. 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 1992

Authors and Affiliations

  • G. A. Kennett
    • 1
  1. 1.SmithKline Beecham PharmaceuticalsHarlowUK

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