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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Dec;116(7):2989–2999. doi: 10.1111/j.1476-5381.1995.tb15954.x

Behavioural interactions between 5-hydroxytryptophan, neuroleptic agents and 5-HT receptor antagonists in modifying rodent responding to aversive situations.

B Costall 1, R J Naylor 1
PMCID: PMC1909209  PMID: 8680734

Abstract

1. The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2. The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test. 3. The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents, spiperone, haloperidol and benperidol, and the atypical neuroleptic agent, clozapine, when administered alone failed to modify mouse or rat behaviour. In contrast, when administered alone, sulpiride in rats and mice and thioridazine in rats disinhibited behaviour. 4. Methysergide, RP62203, ketanserin, ritanserin and MDL11939 antagonized the inhibitory effects of 5-hydroxytryptophan or reversed the inhibitory effects to one of disinhibition. 5. Low doses of spiperone (but not haloperidol or benperidol) also antagonized the inhibitory effects of 5-hydroxytryptophan in the rat but not the mouse. Higher doses of the three neuroleptic agents caused locomotor depression in both rats and mice which obscured any specific changes in behavioural responding to the aversive situations. 6. The disinhibitory profile of sulpiride in both mice and rats and thioridazine in rats was evident during their interaction with 5-hydroxytryptophan. Thioridazine in the mouse and clozapine in rats and mice also reversed the inhibitory effects of 5-hydroxytryptophan to one of disinhibition. 7. In summary, we present evidence that the atypical neuroleptic agents, thioridazine and clozapine, with their known affinity for the 5-HT2 receptors, can mimic the actions of reference 5-HT2 receptor antagonists to antagonize the inhibitory effects of 5-hydroxytryptophan in rodent models of anxiety. The results are intepreted in terms of drug action on different 5-HT2 and other 5-HT receptor subtypes. In addition, thioridazine and sulpiride have disinhibitory effects in their own right which remain to be explained.

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Selected References

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  1. Baxter G., Kennett G., Blaney F., Blackburn T. 5-HT2 receptor subtypes: a family re-united? Trends Pharmacol Sci. 1995 Mar;16(3):105–110. doi: 10.1016/s0165-6147(00)88991-9. [DOI] [PubMed] [Google Scholar]
  2. Castelão J. F., Ferreira L., Gelders Y. G., Heylen S. L. The efficacy of the D2 and 5-HT2 antagonist risperidone (R 64,766) in the treatment of chronic psychosis. An open dose-finding study. Schizophr Res. 1989 Jul-Oct;2(4-5):411–415. doi: 10.1016/0920-9964(89)90034-0. [DOI] [PubMed] [Google Scholar]
  3. Cheng C. H., Costall B., Kelly M. E., Naylor R. J. Actions of 5-hydroxytryptophan to inhibit and disinhibit mouse behaviour in the light/dark test. Eur J Pharmacol. 1994 Apr 1;255(1-3):39–49. doi: 10.1016/0014-2999(94)90080-9. [DOI] [PubMed] [Google Scholar]
  4. Claghorn J., Honigfeld G., Abuzzahab F. S., Sr, Wang R., Steinbook R., Tuason V., Klerman G. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol. 1987 Dec;7(6):377–384. [PubMed] [Google Scholar]
  5. Costall B., Fortune D. H., Naylor R. J., Mardsen C. D., Pycock C. Serotonergic involvement with neuroleptic catalepsy. Neuropharmacology. 1975 Nov;14(11):859–868. doi: 10.1016/0028-3908(75)90114-8. [DOI] [PubMed] [Google Scholar]
  6. Costall B., Hendrie C. A., Kelly M. E., Naylor R. J. Actions of sulpiride and tiapride in a simple model of anxiety in mice. Neuropharmacology. 1987 Feb-Mar;26(2-3):195–200. doi: 10.1016/0028-3908(87)90209-7. [DOI] [PubMed] [Google Scholar]
  7. Costall B., Naylor R. J. Antagonism of the hyperactivity induced by dopamine applied intracerebrally to the nucleus accumbens septi by typical neuroleptics and by clozapine, sulpiride and thioridazine. Eur J Pharmacol. 1976 Jan;35(1):161–168. doi: 10.1016/0014-2999(76)90311-3. [DOI] [PubMed] [Google Scholar]
  8. Costall B., Naylor R. J., Tyers M. B. The psychopharmacology of 5-HT3 receptors. Pharmacol Ther. 1990;47(2):181–202. doi: 10.1016/0163-7258(90)90086-h. [DOI] [PubMed] [Google Scholar]
  9. Doble A., Girdlestone D., Piot O., Allam D., Betschart J., Boireau A., Dupuy A., Guérémy C., Ménager J., Zundel J. L. Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist. Br J Pharmacol. 1992 Jan;105(1):27–36. doi: 10.1111/j.1476-5381.1992.tb14206.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. File S. E., Andrews N., Wu P. Y., Zharkovsky A., Zangrossi H., Jr Modification of chlordiazepoxide's behavioural and neurochemical effects by handling and plus-maze experience. Eur J Pharmacol. 1992 Jul 21;218(1):9–14. doi: 10.1016/0014-2999(92)90141-p. [DOI] [PubMed] [Google Scholar]
  11. File S. E. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods. 1980 Jun;2(3):219–238. doi: 10.1016/0165-0270(80)90012-6. [DOI] [PubMed] [Google Scholar]
  12. Fischer-Cornelssen K. A., Ferner U. J. An example of European multicenter trials: multispectral analysis of clozapine. Psychopharmacol Bull. 1976 Apr;12(2):34–39. [PubMed] [Google Scholar]
  13. Gardner C. R. Recent developments in 5HT-related pharmacology of animal models of anxiety. Pharmacol Biochem Behav. 1986 May;24(5):1479–1485. doi: 10.1016/0091-3057(86)90215-7. [DOI] [PubMed] [Google Scholar]
  14. Janssen P. A. Does ritanserin, a potent serotonin-S2 antagonist, restore energetic functions during the night? J R Soc Med. 1987 Jul;80(7):409–413. doi: 10.1177/014107688708000706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Janssen P. A., Niemegeers C. J., Awouters F., Schellekens K. H., Megens A. A., Meert T. F. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther. 1988 Feb;244(2):685–693. [PubMed] [Google Scholar]
  16. Janssen P. A., Niemegeers C. J., Schellekens K. H., Lenaerts F. M. Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? IV. An improved experimental design for measuring the inhibitory effects of neuroleptic drugs on amphetamine-or apomorphine-induced "Cheroing" and "agitation" in rats. Arzneimittelforschung. 1967 Jul;17(7):841–854. [PubMed] [Google Scholar]
  17. Kane J., Honigfeld G., Singer J., Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988 Sep;45(9):789–796. doi: 10.1001/archpsyc.1988.01800330013001. [DOI] [PubMed] [Google Scholar]
  18. Kennett G. A. 5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model. Psychopharmacology (Berl) 1992;107(2-3):379–384. doi: 10.1007/BF02245165. [DOI] [PubMed] [Google Scholar]
  19. Kennett G. A., Whitton P., Shah K., Curzon G. Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Eur J Pharmacol. 1989 May 30;164(3):445–454. doi: 10.1016/0014-2999(89)90252-5. [DOI] [PubMed] [Google Scholar]
  20. Kennett G. A., Wood M. D., Glen A., Grewal S., Forbes I., Gadre A., Blackburn T. P. In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. Br J Pharmacol. 1994 Mar;111(3):797–802. doi: 10.1111/j.1476-5381.1994.tb14808.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lal H., Prather P. L., Rezazadeh S. M. Potential role of 5HT1C and/or 5HT2 receptors in the mianserin-induced prevention of anxiogenic behaviors occurring during ethanol withdrawal. Alcohol Clin Exp Res. 1993 Apr;17(2):411–417. doi: 10.1111/j.1530-0277.1993.tb00785.x. [DOI] [PubMed] [Google Scholar]
  22. Leysen J. E., Janssen P. M., Schotte A., Luyten W. H., Megens A. A. Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology (Berl) 1993;112(1 Suppl):S40–S54. doi: 10.1007/BF02245006. [DOI] [PubMed] [Google Scholar]
  23. Lovenberg T. W., Baron B. M., de Lecea L., Miller J. D., Prosser R. A., Rea M. A., Foye P. E., Racke M., Slone A. L., Siegel B. W. A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron. 1993 Sep;11(3):449–458. doi: 10.1016/0896-6273(93)90149-l. [DOI] [PubMed] [Google Scholar]
  24. Lund A., Mjellem N. Chronic, combined treatment with desipramine and mianserin: enhanced 5-HT1A receptor function and altered 5-HT1A/5-HT2 receptor interaction in rats. Pharmacol Biochem Behav. 1993 Aug;45(4):777–783. doi: 10.1016/0091-3057(93)90120-i. [DOI] [PubMed] [Google Scholar]
  25. Meltzer H. Y. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 1989;99 (Suppl):S18–S27. doi: 10.1007/BF00442554. [DOI] [PubMed] [Google Scholar]
  26. Mesotten F., Suy E., Pietquin M., Burton P., Heylen S., Gelders Y. Therapeutic effect and safety of increasing doses of risperidone (R 64766) in psychotic patients. Psychopharmacology (Berl) 1989;99(4):445–449. doi: 10.1007/BF00589890. [DOI] [PubMed] [Google Scholar]
  27. Niesink R. J., Van Ree J. M. Antidepressant drugs normalize the increased social behaviour of pairs of male rats induced by short term isolation. Neuropharmacology. 1982 Dec;21(12):1343–1348. doi: 10.1016/0028-3908(82)90144-7. [DOI] [PubMed] [Google Scholar]
  28. Pierce P. A., Kim J. Y., Peroutka S. J. Molecular structural basis of ligand selectivity for 5-HT2 versus 5-HT1C cortical receptors. Naunyn Schmiedebergs Arch Pharmacol. 1992 Jul;346(1):4–11. doi: 10.1007/BF00167563. [DOI] [PubMed] [Google Scholar]
  29. Robertson M. M., Trimble M. R. Major tranquillisers used as antidepressants. A review. J Affect Disord. 1982 Sep;4(3):173–193. doi: 10.1016/0165-0327(82)90002-7. [DOI] [PubMed] [Google Scholar]
  30. Standish-Barry H. M., Bouras N., Bridges P. K., Watson J. P. A randomized double blind group comparative study of sulpiride and amitriptyline in affective disorder. Psychopharmacology (Berl) 1983;81(3):258–260. doi: 10.1007/BF00427274. [DOI] [PubMed] [Google Scholar]
  31. Vanderwolf C. H. A general role for serotonin in the control of behavior: studies with intracerebral 5,7-dihydroxytryptamine. Brain Res. 1989 Dec 18;504(2):192–198. doi: 10.1016/0006-8993(89)91356-5. [DOI] [PubMed] [Google Scholar]
  32. Zifa E., Fillion G. 5-Hydroxytryptamine receptors. Pharmacol Rev. 1992 Sep;44(3):401–458. [PubMed] [Google Scholar]
  33. Zuardi A. W. 5-HT-related drugs and human experimental anxiety. Neurosci Biobehav Rev. 1990 Winter;14(4):507–510. doi: 10.1016/s0149-7634(05)80075-2. [DOI] [PubMed] [Google Scholar]

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