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Dyskinesia pp 182-190 | Cite as

Pharmacological Differentiation of Dopamine D-1 and D-2 Antagonists After Single and Repeated Administration

  • A. V. Christensen
  • J. Arnt
  • O. Svendsen
Part of the Psychopharmacology Supplementum book series (PSYCHOPHARM, volume 2)

Abstract

In single-dose experiments neuroleptics antagonize dopamine (DA)-agonist-induced stereotypies in animals. The antagonistic potency correlates with their clinical antipsychotic effects.

In a series of experiments where DA-agonist-induced stereotyped gnawing in mice and rats was inhibited by neuroleptics it was shown that the antagonistic effect of butyrophenones was greatly attenuated by concomitant treatment with anticholinergics. The effect of phenothiazines was slightly attenuated and that of thioxanthenes and SCH 23390 remained unchanged. After repeated administration a differentiation is also seen in the ability of the antagonists to suppress DA-agonist-induced stereotypies.

The differentiation in these experiments is similar to that seen in dopamine D-1 and D-2 receptor binding. The compounds can be classified into three pharmacological subgroups: butyrophenones (e.g., haloperidol) with affinity for D-2 receptors; phenothiazines (e.g., fluphenazine and perphenazine) with affinity for both D-2 and D-1 receptors but with preference for the D-2 receptors; and thioxanthenes (e.g., cis(Z)-flupentixol and cis(Z)-clopenthixol) with equal affinity for D-1 and D-2 receptors, and the selective D-1 antagonist SCH 23390. This compound has the same antistereotypic effect as is seen with the neuroleptics. We have also investigated the effect of the above-mentioned neuroleptics and SCH 23390 after 12 days’ treatment and 3–5 days withdrawal. They were given either alone or in combination. When they were given alone a clear differentiation was seen between the groups when mice were tested for methylphenidate antagonism. The thioxanthenes and SCH 23390 retain their ability to antagonize the stereotyped gnawing; the phenothiazines show a reduced effect; and the butyrophenones have almost lost their ability to antagonize the stereotyped behavior.

Keywords

Acta Pharmacol Toxicol Cataleptic Effect Antagonistic Potency Avoidance Response Inhibition Pharmacological Subgroup 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Arnt J (1982) Pharmacological specificity of conditioned avoidance response inhibition in rats: inhibition by neuroleptics and correlation to dopamine receptor blockade. Acta Pharmacol Toxicol 51: 321–329CrossRefGoogle Scholar
  2. Arnt J, Christensen AV (1981) Differential reversal by scopolamine and THIP of the antistereotypic and cataleptic effects of neuroleptics. Eur J Pharmacol 69: 107–111PubMedCrossRefGoogle Scholar
  3. Arnt J, Hyttel J (1984) Differential inhibition by dopamine D-1 and D-2 antagonists of circling behavior induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions. Eur J Pharmacol 102: 349–354PubMedCrossRefGoogle Scholar
  4. Arnt J, Christensen AV, Hyttel J (1981) Differential reversal by scopolamine of effects of neuroleptics in rats. Relevance for evaluation of therapeutic and extrapyramidal side-effect potential. Neuropharmacology 20: 1331–1334PubMedGoogle Scholar
  5. Christensen AY, Hyttel J (1982) Neuroleptics and the clinical implications of adaptation of dopamine neurons. Pharm Int 3: 329–332Google Scholar
  6. Christensen AV, Møller Nielsen I (1980) On the supersensitivity of DA receptors after single and repeated administration of neuroleptics. In: Smith RC (ed) Tardive dyskinesia, research and treatment. Spectrum, New York, pp 35–50Google Scholar
  7. Christensen AV, Fjalland B, Møller Nielsen I (1976) On the supersensitivity of dopamine receptors, induced by neuroleptics. Psychopharmacology 48: 1–6PubMedCrossRefGoogle Scholar
  8. Christensen AV, Arnt J, Scheel-Krüger J (1979) Decreased antistereotypic effect of neuroleptics after additional treatment with a benzodiazepine, a GABA agonist or an anticholinergic compound. Life Sci 24: 1395–1402PubMedCrossRefGoogle Scholar
  9. Christensen AV, Arnt J, Scheel-Krüger J (1980) GABA-dopamine/neuroleptic interaction after systemic administration. Brain Res Bull 5 [Suppl 2]: 885–890CrossRefGoogle Scholar
  10. Christensen AV, Arnt J, Svendsen O (1984a) Animal models for neuroleptic induced neurological dysfunction. In: Usdin E (ed) Catecholamines 3. Liss, New York, pp 316–328Google Scholar
  11. Christensen AV, Arnt J, Hyttel J, Svendsen O (1984b) Behavioral correlates to the dopamine D-1 and D-2 antagonists. Pol J Pharmacol Pharm 36: 245–260Google Scholar
  12. Christensen AV, Arnt J, Hyttel J, Larsen J-J, Svendsen O (1984c) Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics. Life Sci 34: 1529–1540PubMedCrossRefGoogle Scholar
  13. Clow A, Jenner P, Marsden CD (1979a) Changes in dopamine-mediated behavior during one year’s neuroleptic administration. Eur J Pharmacol 57: 365–375PubMedCrossRefGoogle Scholar
  14. Clow A, Jenner P, Theodorou A, Marsden CD (1979b) Striatal dopamine receptors become supersensitive while rats are given trifluoperazine for six months. Nature 278: 59–61PubMedCrossRefGoogle Scholar
  15. Dunstan R, Jackson DM (1976) The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol. Psychopharmacology 48: 105–114PubMedCrossRefGoogle Scholar
  16. Dunstan R, Jackson DM (1977) The effect of apomorphine and clonidine on locomotor activity in mice after long-term treatment with haloperidol. Clin Exp Pharmacol Physiol 4: 131–141PubMedCrossRefGoogle Scholar
  17. Gerlach J (1979) Tardive dyskinesia. Dan Med Bull 26: 209–245PubMedGoogle Scholar
  18. Hyttel J (1978) Effects of neuroleptics on 3H-haloperidol and 3H–cis(Z)-flupenthixol binding and on adenylate cyclase activity in vitro. Life Sci 23: 551–556PubMedCrossRefGoogle Scholar
  19. Hyttel J (1983) SCH 23390 - The first selective dopamine D-1 antagonist. Eur J Pharmacol 91: 153–154PubMedCrossRefGoogle Scholar
  20. Iorio LC, Houser V, Korbuda CA, Leitz F, Barnett A (1981) SCH 23390, a benzazepine with atypical effects on dopaminergic systems. Pharmacologist 23: 136Google Scholar
  21. Iorio LC, Barnett A, Leitz FH, Houser VP, Korbuda CA (1983) SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J Pharm Exp Ther 226: 462–468Google Scholar
  22. Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277: 93–96PubMedCrossRefGoogle Scholar
  23. Mogilnicka E, Braestrup C (1976) Noradrenergic influence on the stereotyped behavior induced by amphetamine, phenethylamine and apomorphine. J Pharm Pharmacol 28: 253–255PubMedCrossRefGoogle Scholar
  24. Molander L, Randrup A (1976) Effects of thymoleptics on behavior associated with changes in brain dopamine. II. Modification and potentiation of apomorphine-induced stimulation of mice. Psychopharmacology 49: 139–144PubMedCrossRefGoogle Scholar
  25. Møller Nielsen I, Pedersen V, Nymark M, Franck KF, Boeck V, Fjalland B, Christensen AV (1973) The comparative pharmacology of flupenthixol and some reference neuroleptics. Acta Pharmacol Toxicol 33: 353–362CrossRefGoogle Scholar
  26. Molloy AG, Waddington JL (1984) Dopaminergic behavior stereospecifically promoted by the Dx agonist SK & F 38393 and selectively blocked by the Dx antagonist SCH 23390. Psychopharmacology 82: 409–410PubMedCrossRefGoogle Scholar
  27. Nymark M (1972) Apomorphine provoked stereotypy in the dog. Psychopharmacologia 26: 361–368PubMedCrossRefGoogle Scholar
  28. Pedersen V, Christensen AV (1972) Antagonism of methylphenidate-induced stereotyped gnawing in mice. Acta Pharmacol Toxicol 31: 488–496CrossRefGoogle Scholar
  29. Rosengarten H, Schweitzer JW, Friedhoff AJ (1983) Induction of oral dyskinesias in naive rats by D-1 stimulation. Life Sci 33: 2479–2482PubMedCrossRefGoogle Scholar
  30. Scheel-Krüger J, Cools AR, Honig W (1977) Muscimol antagonizes the ergometrine-induced locomotor activity in nucleus accumbens: evidence for GABA-dopaminergic interaction. Eur J Pharmacol 42: 311–313PubMedCrossRefGoogle Scholar
  31. Scheel-Krüger J, Christensen AV, Arnt J (1978) Muscimol differentially facilitates stereotypy but antagonizes motility induced by dopaminergic drugs: a complex GABA-dopamine interaction. Life Sci 22: 75–84PubMedCrossRefGoogle Scholar
  32. Svendsen O (1979) Long term effect of teflutixol on apomorphine-induced stereotypy and vomiting in dogs. Eur J Pharm 53: 387–390CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1985

Authors and Affiliations

  • A. V. Christensen
  • J. Arnt
  • O. Svendsen
    • 1
  1. 1.H. Lundbeck A/SCopenhagen-ValbyDenmark

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