, Volume 112, Issue 2–3, pp 389–397 | Cite as

Chronic treatment with the D1 receptor antagonist, SCH 23390, and the D2 receptor antagonist, raclopride, in cebus monkeys withdrawn from previous haloperidol treatment

Extrapyramidal syndromes and dopaminergic supersensitivity
  • Henrik Lublin
  • Jes Gerlach
  • Linda Peacock
Original Investigations


The effects of chronic treatment with dopamine (DA) D1 and D2 receptor antagonists were evaluated in eightcebus apella monkeys with mild oral dyskinesia after previous haloperidol treatment. SCH 23390 (D1 antagonist) was given daily to investigate the direct behavioural effect during long-term treatment and the subsequent supersensitivity to DA agonists. Raclopride (D2 antagonist) was investigated for comparison. All drugs were given subcutaneously. SCH 23390 and raclopride induced dystonic syndromes, catalepsy, sedation and reduced locomotor activity. The monkeys developed marked tolerance to the dystonic effect of SCH 23390, while they showed increased sensibility to the dystonic effect of raclopride. Baseline oral dyskinesia (24 h after injection) remained unchanged during D1 antagonist treatment, while it increased during D2 antagonist treatment. SCH 23390 induced supersensitivity to the oral dyskinesia- and grooming-inducing effects of SKF 81297 (D1 agonist) after 9 weeks, while the subsequent treatment with raclopride induced supersensitivity to the reactivity- and stereotypy-inducing effects of quinpirole (D2 receptor agonist) after 3 weeks. Because of the possibility of a carry-over effect (SKF 81297-induced oral hyperkinesia and grooming), other changes in raclopride-induced behaviours cannot be ruled out. The development of tolerance to the dystonic effect of SCH 23390 and the unchanged baseline oral dyskinesia during SCH 23390 treatment indicate an advantageous profile of side effects of DA D1 receptor blockade.

Key words

D1 receptors D2 receptors Extrapyramidal side effects Dopaminergic supersensitivity SCH 23390 Raclopride SKF 81297 Quinpirole Monkeys 


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  1. Adler LA, Angrist B, Reiter S, Rotrosen J (1989) Neuroleptic-induced akathisia: a review. Psychopharmacology 97:1–11Google Scholar
  2. Amalric M, Koob GF, Creese I, Swerdlow NE (1986) Selective D-1 and D-2 receptor antagonists fail to differentially alter super-sensitive locomotor behaviour in rats. Life Sci 39:1985–1993Google Scholar
  3. Andersen PH, Grønvald FC, Hohlweg R, Hansen LB, Guddal E, Braestrup C, Nielsen EB (1992) NNC-112, NNC-687 and NNC 756, new selective and highly potent dopamine D1 receptor antagonists. Eur J Pharmacol 219:45–52Google Scholar
  4. Andersson U, Eckernäs S-A, Hartvig P, Ulin J, Langström B, Haggström JE (1990) Striatal binding of 11C-NMSP studied with positron emission tomography in patients with persistent tardive dyskinesia: no evidence for altered dopamine D2 receptor binding. J Neural Transm 79:215–226Google Scholar
  5. Arnt J, Hyttel J, Perregaard J (1987) Dopamine D-1 receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behaviour in rat. Eur J Pharmacol 133:137–145Google Scholar
  6. Baldessarini RJ, Cole JM, Davis JM et al. (1980) Tardive dyskinesia: a task force report. American Psychiatric, WashingtonGoogle Scholar
  7. Bernardi MM, De Souza H, Palermo-Neto J (1981) Effects of single and long-term haloperidol administration on open-field behaviour of rats. Psychopharmacology 73:171–175Google Scholar
  8. Blin J, Baron JC, Cambon H, Bonnet AM, Dubois B, Loch C, Mazière B, Agid Y (1989) Striatal dopamine D2 receptors in tardive dyskinesia: PET study. J Neurol Neurosurg Psychiatry 52:1248–1252Google Scholar
  9. Braun AR, Chase TN (1988) Behavioral effects of chronic exposure to selective D-1 and D-2 dopamine receptor agonists. Eur Pharmacol 147:441–451Google Scholar
  10. Casey DE (1990) Extrapyramidal syndromes decrease in monkeys during repeated D1 and D2 antagonist treatment. Proc Soc Biol Psychiatry 225:141A-142AGoogle Scholar
  11. Casey DE (1992) Dopamine D1 (SCH 23390) and D2 (haloperidol) antagonists in drug-naive monkeys. Psychopharmacology 107:18–22Google Scholar
  12. Christensen AV (1990) Long-term effects of dopamine D1 and D2 antagonists in vervet monkeys. Behav Neurol 3:49–60Google Scholar
  13. Christensen AV, Arnt J, Hyttel J, Svendsen O (1984a) Behavioral correlates to dopamine D-1 and D-2 antagonists. Pol J Pharmacol Pharm 36:249–264Google Scholar
  14. Christensen AV, Arnt J, Hyttel J, Larsen J-J, Svendsen O (1984b) Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics. Life Sci 34:1529–1540Google Scholar
  15. Christensen AV, Arnt J, Svendsen O (1985) Pharmacological differentiation of dopamine D-1 and D-2 antagonists after single and repeated administration. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia. Research and treatment. Springer, Berlin Heidelberg New York, pp 182–190Google Scholar
  16. Clark D, White FJ (1987) D1 dopamine receptor — the search for a function: a critical evaluation of the D1/D2 dopamine receptor classification and its functional implications. Synapse 1:347–388Google Scholar
  17. Coffin VL, Latranyi MB, Chipkin RE (1989) Acute extrapyramidal syndromes inCebus monkeys: development mediated by dopamine D2 but not D1 receptors. J Pharmacol Exp Ther 249:769–774Google Scholar
  18. Creese I, Chen A (1985) Selective D-1 dopamine receptor increase following chronic treatment with SCH 23390. Eur J Pharmacol 109:127–128Google Scholar
  19. Dreher JK, Jackson DM (1989) Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats. Brain Res 487:267–277Google Scholar
  20. Ellison G, Johansson P, Levin E, See R, Gunne L (1988) Chronic neuroleptics alter the effects of the D1 agonist SK&F 38392 and the D2 agonist LY171555 on oral movements in rats. Psychopharmacology 96:253–257Google Scholar
  21. Felicio LF, Nasello AG, Palermo-Neto J (1987) Dopaminergic supersensitivity after long-term bromopride treatment. Physiol Behav 41:433–437Google Scholar
  22. Gerhardt S, Gerber R, Liebman JM (1985) SCH 23390 dissociated from conventional neuroleptics in apomorphine climbing and primate acute dyskinesia models. Life Sci 37:2355–2363Google Scholar
  23. Gerlach J, Casey D (1988) Tardive dyskinesia. Acta Psychiatr Scand 77:369–378Google Scholar
  24. Hess EJ, Albers LJ, Le H, Creese I (1986) Effects of chronic SCH23390 treatment on the biochemical and behavioral properties of D1 and D2 dopamine receptors: potentiated behavioural responses to a D2 dopamine agonist after selective D1 dopamine receptor upregulation. J Pharmacol Exp Ther 238:846–854Google Scholar
  25. Hyttel J (1983) SCH 23390 — the first selective dopamine D-1 antagonist. Eur J Pharmacol 91:153–154Google Scholar
  26. Hyttel J, Arnt J, van den Berghe M (1989) Selective dopamine D1 and D2 receptor antagonists. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry (Psychopharmacology Servies, vol 7). Springer, Berlin Heidelberg New York, pp 109–122Google Scholar
  27. 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
  28. Kistrup K, Gerlach J (1987) Selective D-1 and D-2 receptor manipulation inCebus monkeys: relevance for dystonia and dyskinesia in humans. Pharmacol Toxicol 61:157–162Google Scholar
  29. Korsgaard S, Gerlach J, Christensson E (1985) Behavioral aspects of serotonin-dopamine interaction in the monkey. Eur J Pharmacol 118:245–252Google Scholar
  30. Liebman J, Neale R (1980) Neuroleptic-induced acute dyskinesia in squirrel monkeys: correlation with propensity to cause extrapyramidal side-effect. Psychopharmacology 68:25–29Google Scholar
  31. Longoni R, Spina L, Di Chiara G (1987) Permissive role of D-1 receptor stimulation for the expression of D-2 mediated behavioral responses: a quantitative phenomenological study in rats. Life Sci 41:2135–2145Google Scholar
  32. Lublin H, Gerlach J (1988) Behavioural effects of dopamine D-1 and D-2 receptor agonists in monkeys previously treated with haloperidol. Eur J Pharmacol 153:239–245Google Scholar
  33. Lublin H, Gerlach J, Peacock L (1992) Effect of D1 and D2 agonists in primates withdrawn from long-term treatment with haloperidol. The potential role of dopamine D1 receptors in dyskinesia. Clin Neuropharmacol 15:448–458Google Scholar
  34. Lublin H, Gerlach J, Mørkeberg F (to be published) Long-term treatment with low doses of the D1 antagonist NNC 756 and the D2 antagonist raclopride in monkeys previously exposed to dopamine antagonistsGoogle Scholar
  35. Löschmann P-A, Smith LA, Lange KW, Jaehnig P, Jenner P, Marsden CD (1991) Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal marmosets. Psychopharmacology 105:303–309Google Scholar
  36. Maldonado R, Baamonde A, Dauge V, Féger J (1990) Effects induced by chronic treatment with selective D1 or D2 antagonists on open-field behaviour and colonic temperature. Fundam Clin Pharmacol 4:341–356Google Scholar
  37. Mashurano M, Waddington JL (1986) Stereotyped behaviour in response to the selective D-2 dopamine receptor agonist RU 24213 is enhanced by pretreatment with the selective D-1 agonist SK&F 38393. Neuropharmacology 25:947–949Google Scholar
  38. McHugh D, Coffin V (1991) The reversal of extrapyramidal side effects with SCH 39166, a dopamine D1 receptor antagonists. Eur J Pharmacol 202:133–134Google Scholar
  39. Memo M, Pizza M, Nisoli E, Missale C, Carruba MO, Spano P (1987) Repeated administration of (−) sulpiride and SCH 23390 differentially up-regulate D1 and D2 receptor function in rat mesostriatal areas but not in cortico-limbic brain regions. Eur J Pharmacol 138:45–51Google Scholar
  40. Morelli M, Di Chiara G (1985) Catalepsy induced by Sch 23390 in rats. Eur J Pharmacol 117:179–185Google Scholar
  41. Murray AM, Waddington JL (1989a) The induction of grooming and vacuous chewing by a series of selective D-1 dopamine receptor agonists: two directions of D-1:D-2 interaction. Eur J Pharmacol 160:377–384Google Scholar
  42. Murray AM, Waddington JL (1989b) Further evidence for two directions of D-1:D-2 dopamine receptor interaction revealed concurrently in distinct elements of typical and atypical behaviour: studies with the new enantioselective D-2 agonist LY 163502. Psychopharmacology 98:245–250Google Scholar
  43. Neale R, Gerhardt S, Fallon S, Liebman JM (1982) Progressive changes in the acute dyskinetic syndrome as a function of repeated elicitation in squirrel monkeys. Psychopharmacology 77:223–228Google Scholar
  44. Nielsen Eb, Andersen PH (1992) Dopamine receptor occupancy in vivo: behavioral correlates using NNC-112, NNC-687 and NNC-756, new selective D1 receptor antagonists. Eur J Pharmacol 219:35–44Google Scholar
  45. Palermo-Neto J (1984) Supersensitivity, drug withdrawal and open-field behaviour. Psychopharmacol Bull 18:11–12Google Scholar
  46. 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
  47. Pich EM, Benfenati F, Farabegoli C, Fuxe K, Meller E, Aronsson M, Goldstein M, Agnati LF (1987) Chronic haloperidol affects striatal D2-dopamine receptor reappearance after irreversible receptor blockade. Brain Res 435:147–152Google Scholar
  48. Pitts DK, Freeman AS, Kelland MD, Chiodo LA (1989) Repeated amphetamine: reduced dopamine neuronal responsiveness to apomorphine but not quinpirole. Eur J Pharmacol 162:167–171Google Scholar
  49. Porceddu ML, Ongini E, Biggio G (1985) (3H)SCH 23390 binding sites increase after chronic blockade of D-1 dopamine receptors. Eur J Pharmacol 118:367–370Google Scholar
  50. Rupniak NMJ, Jenner P, Marsden CD (1986) Acute dystonia induced by neuroleptic drugs. Psychopharmacology 88:403–419Google Scholar
  51. Sanger DJ (1987) The actions of SCH 23390, a D1 receptor antagonist, on operant and avoidance behaviour in rats. Pharmacol Biochem Behav 26:509–514Google Scholar
  52. Seeman P (1980) Brain dopamine receptors. Pharmacol Rev 32:229–313Google Scholar
  53. Sibley DR, Monsma Jr FJ (1992) Molecular biology of dopamine receptors. TIPS 13:61–69Google Scholar
  54. Smialowski A, Bijak M (1989) Repeated administration of SCH 23390 enhances the SKF 38393-induced inhibition in the rat hippocampus. Neuroscience 28:409–412Google Scholar
  55. Snyder SH (1990) The dopamine connection. Nature 347:121–122Google Scholar
  56. Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151Google Scholar
  57. Starr BS, Starr MS (1986) Differential effects of dopamine D1 and D2 agonists and antagonists on velocity of movement, rearing and grooming in the mouse. Neuropharmacology 25:455–463Google Scholar
  58. van Tol HHM, Benzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Cinelli O (1991) Cloning of gene for human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614Google Scholar
  59. Waddington JL (1988) Minireview. Therapeutic potential of selective D-1 dopamine receptor agonists and antagonists in psychiatry and neurology. Gen Pharmacol 19:55–60Google Scholar
  60. Weiss B, Santelli S (1978) Dyskinesia evoked in monkeys by weekly administration of haloperidol. Science 200:799–801Google Scholar
  61. Wilcox RE, Severson JA, Woodward JJ, Randal PK, Vaughn DM, Riffee WH (1990) Behavioral sensitization following a single apomorphine pretreatment — selective effects on the dopamine release process. Brain Res 528:109–113Google Scholar
  62. Williams JEG, Sutherland JV, Woolverton WL (1990) Evaluation of the interaction between D1 and D2 receptors in a drug discrimination paradigm. Behav Neur Biol 53:378–392Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Henrik Lublin
    • 1
  • Jes Gerlach
  • Linda Peacock
  1. 1.Department P and Research Institute of Biological PsychiatrySt Hans HospitalRoskildeDenmark

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