Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity


The Ki values for etoperidone, trazodone and MCPP (m-chlorophenylpiperazine dihydrochloride) at 5-HT1A sites (using rat cerebral cortical synaptosomes and [3H]8-OH-DPAT) were determined to be 20.2, 23.6 and 18.9 nM, respectively. In an effort to elucidate the functional nature of the interaction at 5-HT1A sites in vivo, the ability of each compound to elicit reciprocal forepaw treading (RFT) or to block the RFT induced by 8-OH-DPAT in reserpinized rats was tested. Specifically, 8-OH-DPAT (1.0 mg/kg SC)-challenged or non-challenged (control) reserpinized (1.0 mg/kg SC) rats were administered etoperidone, trazodone or MCPP (IP) and scored for the elicitation of RFT (indicative of 5-HT1A agonistic activity) or for block of RFT induced by 8-OH-DPAT (indicative of 5-HT1A antagonistic activity). Reference compounds confirmed the specificity of the test. We report that etoperidone, trazodone and MCPP inhibited 8-OH-DPAT-induced RFT (ID50=17.4, 23.8 and 13.4 mg/kg, respectively). Only marginal RFT was produced in non-challenged animals by etoperidone and trazodone at a high dose (40 mg/kg). Taken together, the results suggest a predominant antagonistic activity of etoperidone, trazodone and MCPP at 5-HT1A receptor sites in rat central nervous system. However, one cannot rule out the possibility that these compounds are weak partial agonists. This activity may be relevant to the antidepressant action of these compounds.

This is a preview of subscription content, log in to check access.


  1. Arvidsson L-E, Hacksell U, Nilsson JLG, Hjorth S, Carlsson A, Lindberg P, Sanchez D, Wikstrom H (1981) 8-Hydroxy-2-(di-n-propyamino)tertralin, a new centrally acting 5-hydroxytryptamine receptor agonist. J Med Chem 24:921–923

  2. Bossier JR, Portmann-Cristesco E, Soubrie P, Fichelle J (1974) Pharmacological and biochemical features of trazodone. In: Ban TA, Silverstrini B (eds) Trazodone, modern problems of pharmacopsychiatry, vol 9. Karger, Basel, pp 18–28

  3. Brogden RN, Heel RC, Speight TM, Avery GS (1981) Trazodone: a review of its pharmacological properties and therapeutic use in depression and anxiety. Drugs 21:401–429

  4. Caccia S, Ballabio M, Samanin R, Zanini MG, Garattini S (1981) (-)-m-Chlorophenyl-piperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J Pharm Pharmacol 33:477–478

  5. Cheng Y-C, Prusoff WH (1973) Relationship between the inhibition constant (Ki) and the concentration of the inhibitor which causes 50 percent inhibition (I50) on an enzyme reaction. Biochem Pharmacol 22:3099–3108

  6. Cioli V, Corradino C, Piccinelli D, Rocchi MG, Valeri P (1984) A comparative pharmacological study of trazodone, etoperidone and 1-(m-chlorophenyl)piperazine. Pharmacol Res Comm 16:85–100

  7. Costa E (1982) Perspectives in the molecular mechanisms of antide-pressant action. In: Costa E, Racagni G (eds) Typical and atypical antidepressants: molecular mechanisms. Raven Press, New York, pp 21–26

  8. Crow TJ (1979) Biochemical effects of some new antidepressants: putative mechanisms of antidepressant effect. In: Dumont C (ed) Neuropsychopharmacology. Pergamon Press, New York, pp 177–185

  9. Fong MH, Garattini S, Caccia S (1982) 1-m-Chlorophenylpiperazine is an active metabolite common to the psychotropic drugs trazodone, etoperidone and mepiprazole. J Pharm Pharmacol 34:674–675

  10. Fuller RW (1981) Enhancement of monoaminergic neurotransmission by antidepressant drugs. In: Enna SJ, Malick JB, Richelson E (eds) Antidepressants: neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 1–12

  11. Georgotas A, Forsell TL, Mann JJ, Kim M, Gershon S (1982) Trazodone hydrochloride: a wide spectrum antidepressant with a unique pharmacological profile. A review of its neurochemical effects, pharmacology, clinical efficacy, and toxicology. Pharmacotherapy 2:255–265

  12. Hennies HH, Friderichs E (1984) Influence of etoperidone andm-chlorophenylpiperazine on neurotransmitter systems. Paper presented at IUPHAR 9th International Congress, London

  13. Jacobs BL (1976) An animal behavior model for studying central serotonergic synapses. Life Sci 19:777–786

  14. Janiri L, Salera P, Tempesta E (1986) Inhibitory effects of etoperidone on the spontaneous activity of brainstem neurones and their excitatory responses to some putative transmitters. Arzneimittelforschung 36:1721–1726

  15. Kern U, Richter W (1985) Clinical comparison of etoperidone and amitryptyline in endogenous depressive patients. Pharmacopsychiatry 18:94–95

  16. Koe BK (1975) Effects of antidepressant drugs on brain catecholamines and serotonin. In: Fielding S, Lal H (eds) Antidepressants. Futura Publishing, New York, pp 143–180

  17. Maj J, Palider W, Rawlow A (1979) Trazodone, a central serotonin antagonist and agonist. J Neural Transm 44:237–248

  18. Przegalinski E, Lewandowska A (1979) The effect of etoperidone, a new potential antidepressant drug, on the central serotonin system. J Neural Transm 46:303–312

  19. Silvestrini B, Cioli V, Burberi S, Catanese B (1968) Pharmacological properties of AF 1161, a new psychotropic drug. Int J Neuropharmacol 7:587–599

  20. Stefanini E, Fadda F, Medda L, Gessa GL (1976)' Selective inhibition of serotonin uptake by trazodone, a new antidepressant agent. Life Sci 18:1459–1466

  21. Tricklebank MD (1987) The motor and discriminative stimulus properties of 8-OH-DPAT and their relationship to activation of the putative 5-HT1A receptor. In: Dourish CT Ahlenius S, Hutson PH (eds) Brain 5-HT1A receptors. VCH, New York, pp 140–151

  22. Tricklebank MD, Forler C, Forzard JR (1984) The involvement of subtypes of the 5-HT1 receptor and of catecholaminergic systems in the behavioural response to 8-hydroxy-2-(di-n-propylamino) tetralin in the rat. Eur J Pharmacol 106:271–282

  23. Valeri P, Angelucci L (1977) Inhibition of monoamine uptake in brain by etoperidone. 18th National Congress of the Italian Society of Pharmacology. 1st USSR-Italian Joint meeting, Modena, Italy 1976, Abstract 137

  24. Winer BJ (1971) Statistical principles in experimental design, 2nd edn. McGraw-Hill, New York

Download references

Author information

Correspondence to R. B. Raffa.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Raffa, R.B., Shank, R.P. & Vaught, J.L. Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity. Psychopharmacology 108, 320–326 (1992).

Download citation

Key words

  • Etoperidone
  • Trazodone
  • MCPP
  • Serotonin
  • 5-HT1A
  • RFT (Reciprocal Forepaw Treading)
  • Antagonist
  • Rats