, Volume 107, Issue 1, pp 18–22 | Cite as

Dopamine D1 (SCH 23390) and D2 (haloperidol) antagonists in drug-naive monkeys

  • Daniel E. Casey
Original Investigations


The ability of dopamine D1 antagonists to produce acute extrapyramidal syndromes (EPS) in nonhuman primates is unclear. Some studies in monkeys show that D1 antagonists produce acute dystonia, whereas other studies do not report these effects. The central issues that have yielded conflicting results revolve around prior treatment status (neuroleptic-naive versus neuroleptic sensitized) and route of administration (oral versus parenteral). In this study, separate groups of neuroleptic drug-naive cebus monkeys were tested once weekly with intramuscularly administered SCH 23390, a D1 antagonist, or haloperidol, a D2 antagonist, across a dose range of 0.01–0.25 mg/kg, and a saline control. Both active drugs, but not saline, produced clinically identical syndromes of acute dystonia and bradykinesia, though haloperidol induced higher symptom scores over a longer duration. Sedation and locomotor activity were unchanged by SCH 23390, but decreased with haloperidol. Factors regarding acute EPS liability in nonhuman primate models and clinical implications in man are discussed.

Key words

Neuroleptics Dopamine receptor subtypes SCH 23390 Haloperidol Extrapyramidal syndromes Nonhuman primates 


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  1. Casey DE (1988) Tardive dyskinesia and dopamine receptor hypersensitivity: pros and cons. In: Belmaker RH, Sandler M, Dahlström (eds) Neurology and neurobiology, vol. 42C, Progress in catecholamine research, part C: clinical aspects. Alan R. Liss, New York, pp 9–12Google Scholar
  2. Casey DE (1989a) Clozapine: neuroleptic-induced EPS and tardive dyskinesia. Psychopharmacology 99:S47-S53Google Scholar
  3. Casey DE (1989b) Serotonergic aspects of acute extrapyramidal syndromes in nonhuman primates. Psychopharmacol Bull 25:457–459Google Scholar
  4. Casey DE (1991a) Extrapyramidal syndromes in nonhuman primates: typical and atypical neuroleptics. Psychopharmacol Bull 27:47–50Google Scholar
  5. Casey DE (1991b) SCH 23390 and psychosis. Lancet 338:185Google Scholar
  6. Casey DE (1991c) Neuroleptic drug-induced extrapyramidal syndromes and tardive dyskinesia. Schizophr Res 4:109–120Google Scholar
  7. Casey DE, Keepers GA (1988) Neuroleptic side effects: acute extrapyramidal syndromes and tardive dyskinesia. In: Casey DE, Christensen AV (eds) Psychopharmacology: current trends. Springer, Berlin Heidelberg New York, pp 74–93Google Scholar
  8. Casey DE, Gerlach J, Christensson E (1980) Dopamine, acetylcholine, and GABA effects in acute dystonia in primates. Psychopharmacology 70:83–87Google Scholar
  9. Christensen AV (1990) Long-term effects of dopamine D1 and D2 antagonists in vervet monkeys. Behav Neurol 3:49–60Google Scholar
  10. Christensen AV, Arnt J, Hyttel J, Larsen JJ, Svendsen O (1984) Pharmacological effects of a specific dopamine D1 antagonist SCH 23390 in comparison with neuroleptics. Life Sci 34:1529–1540Google Scholar
  11. Coffin VL, Latranyi MB, Chipkin RE (1989) Acute extrapyramidal syndrome in cebus monkeys: development mediated by dopamine D2 but not D1 receptors. J Pharmacol Exp Ther 249:769–774Google Scholar
  12. Farde L (1992) Selective D1- or D2-dopamine receptor blockade induces akathisia in humans — a PET-study with [11C] SCH 23390 and [11C] raclopride. Psychopharmacology 107:23–29Google Scholar
  13. Farde L, Halldin C, Stone-Elander S, Sedvall G (1987) PET-analysis of human dopamine receptor subtypes using [11C] SCH 23390 and [11C] raclopride. Psychopharmacology 92:278–284Google Scholar
  14. Farde L, Wiesel F-A, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–78Google Scholar
  15. Gerlach J, Lublin H (1988) Tardive dyskinesia may be due to an increased D1/D2 receptor ratio in the brain. Schizophr Res 1:230Google Scholar
  16. Gerlach J, Kistrup K, Korsgaard S (1987) Effect of selective and D2 dopamine receptor antagonists and agonists in cebus monkeys: implications for acute and tardive dyskinesias. In: Dahl SG, Gram LS, Paul SN, Potter WV (eds) Clinical pharmacology in psychiatry. Springer, Berlin Heidelberg New York, pp 236–242Google Scholar
  17. Gessa GL, Canu A, Del Zompo M, Burrai C, Serra G (1991a) Lack of acute antipsychotic effect of SCH 23390, a selective dopamine D1 receptor antagonist. Lancet 337:854–855Google Scholar
  18. Gessa GL, Ganu A, Del Zompo M, Burrai C, Serra G (1991b) SCH 23390 and psychosis. Lancet 338:185–186Google Scholar
  19. Hansen L, Gerlach J (1991) Dopamine 1 and 2 receptor interaction in the development of dystonia and hypersensibility in cebus monkeys. Biol Psychiatry 29:275SGoogle Scholar
  20. Hyttel J (1983) SCH 23390: the first selective dopamine D1 antagonist. Eur J Pharmacol 91:153–154Google Scholar
  21. Iorio LC, Barnett A, Leitz FH, Houser VP, Korduba CA (1983) SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J Pharmacol Exp Ther 226:462–468Google Scholar
  22. Liebman J, Neale R (1980) Neuroleptic-induced acute dyskinesias in squirrel monkeys. Correlation with propensity to cause extrapyramidal side effects. Psychopharmacology 68:25–29Google Scholar
  23. Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin pKi values. J Pharmacol Exp Ther 251:238–246Google Scholar
  24. Peacock, L, Lublin H, Gerlach J (1990) The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment. Eur J Pharmacol 186:49–59Google Scholar
  25. Seeman P, Lee T, Chau-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719Google Scholar
  26. Waddington JL (1986) Behavioral correlates of the action of selective D1 dopamine receptor antagonists. Biochem Pharmacol 35:3661–3667Google Scholar
  27. Waddington JL, O'Boyle KM (1989) Drugs acting on brain dopamine receptors: a conceptual re-evaluation five years after the first selective D1 antagonist. Pharmacol Ther 43:1–52Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Daniel E. Casey
    • 1
  1. 1.Psychiatry Research and PsychopharmacologyVA Medical CenterPortlandUSA

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