Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1975 Nov;72(11):4376–4380. doi: 10.1073/pnas.72.11.4376

Brain receptors for antipsychotic drugs and dopamine: direct binding assays.

P Seeman, M Chau-Wong, J Tedesco, K Wong
PMCID: PMC388724  PMID: 1060115

Abstract

In order to test the suggestion that antipsychotic drugs act by blocking dopamine receptors in the brain, the direct effects of such neuroleptic drugs were tested on the stereospecific binding of [3H]dopamine and of [3H]haloperidol to rat brain striata and their subfractions. The stereospecific component of binding was defined as that amount of [3h]dopamine or [3H]haloperidol bound in the presence of (-)-butaclamol (an inactive drug) minus that bound in the presence of (+)-butaclamol (a potent neuroleptic drug); 100 nM butaclamol was used for the [3H]haloperidol assay, while 1 muM butaclamol was used for the [3H]dopamine assay. Various antipsychotic drugs inhibited this stereospecific component in both the dopamine and haloperidol assays. These inhibitory potencies correlated with the clinical doses used for controlling schizophrenia.

Full text

PDF
4376

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bruderlein F. T., Humber L. G. Neuroleptic agents of the benzocycloheptapyridoisoquinoline series. 1. Syntheses and stereochemical and structural requirements for activity of butaclamol and related compounds. J Med Chem. 1975 Feb;18(2):185–188. doi: 10.1021/jm00236a016. [DOI] [PubMed] [Google Scholar]
  2. Bunney B. S., Walters J. R., Roth R. H., Aghajanian G. K. Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J Pharmacol Exp Ther. 1973 Jun;185(3):560–571. [PubMed] [Google Scholar]
  3. CARLSSON A., LINDQVIST M. EFFECT OF CHLORPROMAZINE OR HALOPERIDOL ON FORMATION OF 3METHOXYTYRAMINE AND NORMETANEPHRINE IN MOUSE BRAIN. Acta Pharmacol Toxicol (Copenh) 1963;20:140–144. doi: 10.1111/j.1600-0773.1963.tb01730.x. [DOI] [PubMed] [Google Scholar]
  4. Chau-Wong M., Seeman P. The control of membrane-bound Ca 2+ by ATP. Biochim Biophys Acta. 1971 Aug 13;241(2):473–482. doi: 10.1016/0005-2736(71)90046-0. [DOI] [PubMed] [Google Scholar]
  5. Clement-Cormier Y. C., Kebabian J. W., Petzold G. L., Greengard P. Dopamine-sensitive adenylate cyclase in mammalian brain: a possible site of action of antipsychotic drugs. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1113–1117. doi: 10.1073/pnas.71.4.1113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coyle J. T., Snyder S. H. Antiparkinsonian drugs: inhibition of dopamine uptake in the corpus striatum as a possible mechanism of action. Science. 1969 Nov 14;166(3907):899–901. doi: 10.1126/science.166.3907.899. [DOI] [PubMed] [Google Scholar]
  7. Cuatrecasas P. Membrane receptors. Annu Rev Biochem. 1974;43(0):169–214. doi: 10.1146/annurev.bi.43.070174.001125. [DOI] [PubMed] [Google Scholar]
  8. Goldstein A., Lowney L. I., Pal B. K. Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain. Proc Natl Acad Sci U S A. 1971 Aug;68(8):1742–1747. doi: 10.1073/pnas.68.8.1742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Harris J. E., Baldessarini R. J. The uptake of (3H)dopamine by homogenates of rat corpus striatum: effects of cations. Life Sci. 1973 Aug 16;13(4):303–312. doi: 10.1016/0024-3205(73)90221-x. [DOI] [PubMed] [Google Scholar]
  10. Heikkila R. E., Orlansky H., Cohen G. Studies on the distinction between uptake inhibition and release of (3H)dopamine in rat brain tissue slices. Biochem Pharmacol. 1975 Apr 15;24(8):847–852. doi: 10.1016/0006-2952(75)90152-5. [DOI] [PubMed] [Google Scholar]
  11. Horn A. S., Snyder S. H. Chlorpromazine and dopamine: conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs. Proc Natl Acad Sci U S A. 1971 Oct;68(10):2325–2328. doi: 10.1073/pnas.68.10.2325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev. 1966 Jun;18(2):925–964. [PubMed] [Google Scholar]
  13. Iversen L. L. Dopamine receptors in the brain. Science. 1975 Jun 13;188(4193):1084–1089. doi: 10.1126/science.2976. [DOI] [PubMed] [Google Scholar]
  14. Janssen P. A., Allewijn F. T. The distribution of the butyrophenones haloperidol, trifluperidol, moperone, and clofluperol in rats, and its relationship with their neuroleptic activity. Arzneimittelforschung. 1969 Feb;19(2):199–208. [PubMed] [Google Scholar]
  15. Karobath M., Leitich H. Antipsychotic drugs and dopamine-stimulated adenylate cyclase prepared from corpus striatum of rat brain. Proc Natl Acad Sci U S A. 1974 Jul;71(7):2915–2918. doi: 10.1073/pnas.71.7.2915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kwant W. O., Seeman P. The displacement of membrane calcium by a local anesthetic (chlorpromazine). Biochim Biophys Acta. 1969;193(2):338–349. doi: 10.1016/0005-2736(69)90194-1. [DOI] [PubMed] [Google Scholar]
  17. Lefkowitz R. J. Commentary. Molecular pharmacology of beta-adrenergic receptors--a status report. Biochem Pharmacol. 1974 Aug;23(15):2069–2076. doi: 10.1016/0006-2952(74)90571-1. [DOI] [PubMed] [Google Scholar]
  18. Levitzki A., Atlas D., Steer M. L. The binding characteristics and number of beta-adrenergic receptors on the turkey erythrocyte. Proc Natl Acad Sci U S A. 1974 Jul;71(7):2773–2776. doi: 10.1073/pnas.71.7.2773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lippmann W., Pugsley T., Merker J. Effect of butaclamol and its enantiomers upon striatal homovanillic acid and adenyl cyclase of olfactory tubercle in rats. Life Sci. 1975 Jan 15;16(2):213–224. doi: 10.1016/0024-3205(75)90019-3. [DOI] [PubMed] [Google Scholar]
  20. Matthysse S. Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Fed Proc. 1973 Feb;32(2):200–205. [PubMed] [Google Scholar]
  21. Mielke D. H., Gallant D. M., Oelsner T., Kessler C. M., Tomlinson W. K., Cohen G. H. Butaclamol hydrochloride (AY-23,028): an early evaluation in severely ill schizophrenics. Dis Nerv Syst. 1975 Jan;36(1):7–8. [PubMed] [Google Scholar]
  22. Pert C. B., Snyder S. H. Opiate receptor: demonstration in nervous tissue. Science. 1973 Mar 9;179(4077):1011–1014. doi: 10.1126/science.179.4077.1011. [DOI] [PubMed] [Google Scholar]
  23. Seeman P., Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975 Jun 20;188(4194):1217–1219. doi: 10.1126/science.1145194. [DOI] [PubMed] [Google Scholar]
  24. Seeman P., Lee T. The dopamine-releasing actions of neuroleptics and ethanol. J Pharmacol Exp Ther. 1974 Jul;190(1):131–140. [PubMed] [Google Scholar]
  25. Seeman P., Roth S., Schneider H. The membrane concentrations of alcohol anesthetics. Biochim Biophys Acta. 1971 Feb 2;225(2):171–184. doi: 10.1016/0005-2736(71)90210-0. [DOI] [PubMed] [Google Scholar]
  26. Seeman P., Staiman A., Chau-Wong M. The nerve impulse-blocking actions of tranquilizers and the binding of neuroleptics to synaptosome membranes. J Pharmacol Exp Ther. 1974 Jul;190(1):123–130. [PubMed] [Google Scholar]
  27. Seeman P. The membrane actions of anesthetics and tranquilizers. Pharmacol Rev. 1972 Dec;24(4):583–655. [PubMed] [Google Scholar]
  28. Snyder S. H., Banerjee S. P., Yamamura H. I., Greenberg D. Drugs, neurotransmitters, and schizophrenia. Science. 1974 Jun 21;184(4143):1243–1253. doi: 10.1126/science.184.4143.1243. [DOI] [PubMed] [Google Scholar]
  29. Taylor K. M. Displacement of bound 14C-fluphenazine by biogenic amines and antipsychotic drugs in homogenates of brain tissue. Nature. 1974 Nov 15;252(5480):238–241. doi: 10.1038/252238a0. [DOI] [PubMed] [Google Scholar]
  30. Terenius L. Letter: A rapid assay of affinity for the narcotic receptor in rat brain: application to methadone analogues. Acta Pharmacol Toxicol (Copenh) 1974 Jan;34(1):88–91. doi: 10.1111/j.1600-0773.1974.tb02016.x. [DOI] [PubMed] [Google Scholar]
  31. Tuomisto L., Tuomisto J., Smissman E. E. Dopamine uptake in striatal and hypothalamic synaptosomes: conformational selectivity of the inhibition. Eur J Pharmacol. 1974 Mar;25(3):351–361. doi: 10.1016/0014-2999(74)90265-9. [DOI] [PubMed] [Google Scholar]
  32. Voith K., Herr F. The behavioral pharmacology of butaclamol hydrochloride (AY-23,028), a new potent neuroleptic drug. Psychopharmacologia. 1975 Apr 30;42(1):11–20. doi: 10.1007/BF00428819. [DOI] [PubMed] [Google Scholar]
  33. van Rossum J. M. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther. 1966 Apr;160(2):492–494. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES