Biochemical and Pharmacological Differentiation of Neuroleptic Effect on Dopamine D-1 and D-2 Receptors

  • J. Hyttel
  • Anne Vibeke Christensen
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 18)


In dopamine (DA) receptor binding tests two different receptor populations can be measured. By using 3H-haloperidol or 3H-spiroperidol as ligands D-2 receptors are detected. When the thioxanthene neuroleptics 3H-cis (Z)-flupenthixol or 3H-piflutixol are used as ligands D-1 receptors coupled to adenylate cyclase can be detected. In displacement experiments butyrophenones (haloperidol and spiroperidol) and diphenylbutylpiperidines (pimozide) interact with D-2 receptors only, whereas thioxanthenes (cis [Z]-flupenthixol, cis [Z]-piflutixol and cis [Z]-clopenthixol) have equal affinity for D-1 and D-2 receptors. A similar differentiation is also seen in behavioral studies. The methylphenidate antagonistic effect of butyrophenones and diphenylbutylpiperidines is dramatically attenuated by concomitant treatment with an anticholinergic agent or a GABA agonist. The effect of thioxanthenes is almost unchanged. When mice are treated for 12 days with neuroleptics, supersensitivity to methylphenidate is induced. The supersensitivity is reversed by thioxanthenes, whereas butyrophenones and diphenylbutylpiperidines have no effect at all. These differenes do not appear to be due to a change in the affinity for DA receptors because the ability of cis (Z)-flupenthixol, haloperidol, DA or apomorphine to displace 3H-piflutixol or 3H-spiroperidol is the same in supersensitive and control mice. The results clearly demonstrate that neuroleptics acting on both D-1 and D-2 receptors have a behavioral profile different from that of neuroleptics acting exclusively on D-2 receptors.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arnt, J., Christensen, A. V: Differential reversal by scopolamine and THIP of the antistereotypic and cataleptic effects of neuroleptics. Eur. J. Pharmacol. 69, 107–111 (1981).CrossRefPubMedGoogle Scholar
  2. Arnt, J., Christensen, A. V., Hyttel, J.: Differential reversal by scopolamine of effects of neuroleptics in rats. Relevance for evaluation of therapeutic and extrapyramidal side-effect potential. Neuropharmac. 20, 1331–1334 (1981).Google Scholar
  3. Burt, D. R., Creese, I., Snyder, S. H.: Properties of (3H)-haloperidol and (3H)-dopamine binding associated with dopamine receptors in calf brain membranes. Mol. Pharmacol. 12, 800–812 (1976).PubMedGoogle Scholar
  4. Burt, D.R., Creese, I., Snyder, S. H.: Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain. Science 196, 326–328 (1977).CrossRefPubMedGoogle Scholar
  5. Christensen, A. V., Arnt, J., Scheel-Krüger, J.: Decreased antistereotypic effect of neuroleptics after additional treatment with a benzodiazepine, a GABA agonist and an anticholinergic compound. Life Sci. 24, 1395–1402 (1979).CrossRefPubMedGoogle Scholar
  6. Christensen, A. V., Ana, I. Scheel-Krüger, J.: GABA-dopamine/neuroleptic interaction after systemic administration. Brain Res. Bull. 5, Suppl. 2, 885–890 (1980).CrossRefGoogle Scholar
  7. Christensen, A. V., Hyttel, J.: Neuroleptics and the clinical implications of adaptation of dopamine neurons. Pharmacy International (in press).Google Scholar
  8. Clow, A., Jenner, P., Marsden, C.D.: Changes in dopamine-mediated behaviour during one year’s neuroleptic administration. Eur. J. Pharmacol. 57, 365–375 (1979).CrossRefPubMedGoogle Scholar
  9. Clow, A., Theodorou, A.,Jenner, P., Marsden, C.D.: Changes in rat striatal dopamine turnover and receptor activity during one years neuroleptic administration. Eur. J. Pharmacol. 63, 135–144 (1980).Google Scholar
  10. Creese, I., Burt, D.R., Snyder, S. H.: Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192, 481–483 (1976).CrossRefPubMedGoogle Scholar
  11. Cross, A.J., Owen, F.: Characteristics of 3H-cis-flupenthixol binding to calf brain membranes. Eur. J. Pharmacol. 65, 341–347 (1980).CrossRefPubMedGoogle Scholar
  12. Fjalland, B., Meller Nielsen, I.: Enhancement of methylphenidate-induced stereotypies by repeated administration of neuroleptics. Psychopharmacologia 34, 105–109 (1974).CrossRefPubMedGoogle Scholar
  13. Fjalland, B., Meller Nielsen, I.: Methylphenidate antagonism of haloperidol, interaction with cholinergic and anticholinergic drugs. Psychopharmacologia 34, 111–118 (1974).CrossRefPubMedGoogle Scholar
  14. Hyttel, J.: Effects of neuroleptics on 3H-haloperidol and 3H-cis (Z)-flupenthixol binding and on adenylate cyclase activity in vitro. Life Sci. 23, 551–556 (1978).CrossRefPubMedGoogle Scholar
  15. Hyttel, J.: A comparison of the effect of neuroleptic drugs on the binding of 3H-haloperidol and 3H-cis (Z)-flupenthixol and on adenylate cyclase activity in rat striatal tissue in vitro. Prog. Neuro-Psychopharmac. 2, 329–335 (1978).CrossRefGoogle Scholar
  16. Hyttel, J.: Similarities between the binding of 3H-piflutixol and 3H-flupenthixol to rat striatal dopamine receptors in vitro. Life Sci. 28, 563–569 (1981).CrossRefPubMedGoogle Scholar
  17. Hyttel, J.: Preferential labelling of adenylate cyclase coupled dopamine receptors with thioxanthene neuroleptics. Advances in the Biosciences 37, 147–152 (1982).Google Scholar
  18. Kebabian, J. W., Calne, D. B.: Multiple receptors for dopamine. Nature 277, 93–96 (1979).CrossRefPubMedGoogle Scholar
  19. Leff, S., Lynne, A., Hyttel,J., Creese, I.: Kainate lesion dissociates striatal dopamine receptor radioligand binding sites. Eur. J. Pharmacol. 70, 71–75 (1981).Google Scholar
  20. Owen, F., Cross, A.J., Waddington, J. L., Poulter, M., Gamble, S.J., Crow, T.J.: Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration. Life Sci. 26, 55–59 (1980).CrossRefPubMedGoogle Scholar
  21. Pedersen, V.: Potentiation of apomorphine effect (compulsive gnawing behaviour) in mice. Acta pharmacol. et toxicol. 25, Suppl. 4, 63 (1967).Google Scholar
  22. Pedersen, V, Christensen, A. V.: Antagonism of methylphenidate-induced stereotyped gnawing in mice. Acta pharmacol. et toxicol. 31, 488–496 (1972).CrossRefGoogle Scholar
  23. Seeman, P.: Brain dopamine receptors. Pharmac. Rev. 32, 229–313 (1980).Google Scholar
  24. Svendsen, O., Hyttel,J., Christensen, A. V.: Biochemical and behavioural effects in rats after prolonged treatment with thioxanthene neuroleptics. Abstract from 13th C.I.N.P. Congres, Israel, Jerusalem, June 20–25, 1982, p. 709.Google Scholar

Copyright information

© Springer-Verlag Wien 1983

Authors and Affiliations

  • J. Hyttel
    • 1
  • Anne Vibeke Christensen
    • 2
  1. 1.Department of Pharmacology and ToxicologyH. Lundbeck & Co. A/SCopenhagen-ValbyDenmark
  2. 2.Department of Pharmacology and ToxicologyH. Lundbeck & Co. A/SCopenhagenDenmark

Personalised recommendations