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Discovering risperidone: the LSD model of psychopathology

  • Nature Reviews Drug Discovery volume 2, pages 315320 (2003)
  • doi:10.1038/nrd1062
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Abstract

In the 1970s and 1980s, Janssen Pharmaceutica Research, which had a broad interest in central nervous system disorders and nurtured intellectual freedom, developed original, and at times heretical, concepts. It took decades for the scientific community to endorse some of these concepts. Among them were such notions as an elementary particle of behaviour, the introduction of response quality in receptor theory, and the idea that tolerance does not develop to opioids. These concepts enabled the discovery of the antipsychotic risperidone, a unique full antagonist of the interoceptive effects of LSD.

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References

  1. 1.

    & Drug Discovery (Humana, Clifton, New Jersey, 1990).

  2. 2.

    , & Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part I: 'Neuroleptic activity spectra' for rats. Drug. Res. 15, 104–117 (1965).

  3. 3.

    , , & Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part IV: An improved experimental design for measuring the inhibitory effects of neuroleptic drugs on amphetamine- or apomorphine-induced 'chewing' and 'agitation' in rats. Drug. Res. 17, 841–854 (1967).

  4. 4.

    in Drug Addiction I (ed. Martin, W. R.) 197–258 (Springer Verlag, New York, 1977).

  5. 5.

    State-dependent learning produced by depressant and atropine-like drugs. Psychopharmacologia 10, 6–31 (1966).

  6. 6.

    , & Theoretical and methodological considerations on drug discrimination learning. Psychopharmacologia 46, 169–177 (1976).

  7. 7.

    The discriminative response: an elementary particle of behavior. Behav. Pharmacol. 2, 283–286 (1991).

  8. 8.

    Drug discrimination in neurobiology. Pharmacol. Biochem. Behav. 64, 337–345 (1999).

  9. 9.

    Discriminative stimulus properties of narcotic analgesic drugs. Pharmacol. Biochem. Behav. 9, 863–887 (1978).

  10. 10.

    , & The narcotic discriminative stimulus complex: relation to analgesic activity. J. Pharm. Pharmacol. 28, 183–187 (1976).

  11. 11.

    , , & Investigations on drug produced and subjectively experienced discriminative stimuli. 1. The fentanyl cue, a tool to investigate subjectively experienced narcotic drug actions. Life Sci. 16, 705–716 (1975).

  12. 12.

    , , & Investigations on drug produced and subjectively experienced discriminative stimuli. 2. Loperamide, an antidiarrheal devoid of narcotic cue producing actions. Life Sci. 16, 717–728 (1975).

  13. 13.

    in Principles of Drug Action: The Basis of Pharmacology (eds Pratt, W. L. & Taylor, P.) 639–690 (Churchill Livingstone, New York, 1990).

  14. 14.

    , , & Discriminative stimulus properties of fentanyl and morphine: tolerance and dependence. Pharmacol. Biochem. Behav. 5, 401–408 (1976).

  15. 15.

    Drug Discrimination: no evidence for tolerance to opiates. Pharmacol. Rev. 47, 605–629 (1995).

  16. 16.

    in Stimulus Properties of Drugs: Ten Years of Progress (eds Colpaert, F. C. & Rosecrans, J.) 301–321 (Elsevier/North Holland Biomedical, Amsterdam, 1978).

  17. 17.

    System theory of pain and of opiate analgesia: no tolerance to opiates. Pharmacol. Rev. 48, 355–402 (1996).

  18. 18.

    Editor's note. Pharmacol. Rev. 48, 353 (1996).

  19. 19.

    The effects of pain on opioid tolerance: how do we resolve the controversy? Pharmacol. Rev. 48, 403–407 (1996).

  20. 20.

    & Paradoxical signal transduction in neurobiological systems. Mol. Neurobiol. 24, 145–168 (2001).

  21. 21.

    et al. Large-amplitude 5-HT1A receptor activation: a new mechanism of profound central analgesia. Neuropharmacology. 43, 945–958 (2002).

  22. 22.

    Affinity and intrinsic activity in the theory of competitive inhibition. Part I. Problems and theory. Arch. Int. Pharmacodyn. Ther. 99, 32–49 (1954).

  23. 23.

    , & On the ability of narcotic antagonists to produce the narcotic cue. J. Pharmacol. Exp. Ther. 197, 180–187 (1976).

  24. 24.

    & Agonist and antagonist effects of prototype opiate drug in rats discriminating fentanyl from saline: characteristics of partial generalization. J. Pharmacol. Exp. Ther. 230, 193–199 (1984).

  25. 25.

    in Drug Discrimination: Applications in CNS Pharmacology (eds Colpaert, F. C. & Slanggen, J. L.) 3–16 (Elsevier Biomedical, Amsterdam, 1982).

  26. 26.

    in Behavioural Analysis of Drug Dependence (eds Goldberg, S. R. & Stolerman, I. P.) 161–193 (Academic, New York, 1986).

  27. 27.

    , & The emergence of the drug receptor theory. Nature Rev. Drug Discov. 1, 637–641 (2002).

  28. 28.

    Pharmacologic Analysis of Drug–Receptor Interaction 3rd edn (Lippincott–Raven, Philadelphia, 1997).

  29. 29.

    Measures of efficacy using G proteins as endpoints: differential engagement of G proteins through single receptors. Mol. Pharmacol. 62, 451–452 (2002).

  30. 30.

    , , & Antibody capture assay reveals bell-shaped concentration-response isotherms for h5-HT(1A) receptor-mediated Gα(i3) activation: conformational selection by high-efficacy agonists, and relationship to trafficking of receptor signalling. Mol. Pharmacol. 62, 590–601 (2002).

  31. 31.

    How do you feel? Interoception: the sense of the physiological condition of the body. Nature Rev. Neurosci. 2, 655–666 (2002).

  32. 32.

    How do you feel? Trends Cogn. Sci. 6, 317–319 (2002).

  33. 33.

    , & In vivo evidence of partial agonist activity exerted by purported 5-hydroxytryptamine antagonists. Eur. J. Pharmacol. 58, 505–509 (1979).

  34. 34.

    , & A drug discrimination analysis of lysergic acid diethylamide: in vivo agonist and antagonist effects of purported 5-hydroxytryptamine antagonists and pirenperone, an LSD-antagonist. J. Pharmacol. Exp. Ther. 221, 206–214 (1982).

  35. 35.

    Efficacy at G-protein-coupled receptors. Nature Rev. Drug Discov. 1, 103–110 (2002).

  36. 36.

    & A systematic study of the pharmacological activities of dopamine antagonists. Life Sci. 24, 2201–2216 (1979).

  37. 37.

    , , & Serotonergic component of neuroleptic receptors. Nature 272, 168–171 (1978).

  38. 38.

    , & Two distinct central serotonin receptors with different physiological functions. Science 212, 827–829 (1981).

  39. 39.

    & Novel 1,2-benzisoxadol-3-yl and 1,2-benzisothiazol-3-yl derivatives. US Patent 4,804,633 (1985).

  40. 40.

    & Effects of the atypical antipsychotic risperidone on hostility and aggression in schizophrenia: a meta-analysis of controlled trials. Eur. Neuropsychopharmacol. 11, 289–293 (2001).

  41. 41.

    , & Treatment of the symptoms of schizophrenia: a combined analysis of double-blind studies comparing risperidone with haloperidol and other antispychotic agents. Int. Clin. Psychopharmacol. 16, 265–274 (2001).

  42. 42.

    Does risperidone have a place in the treatment of nonschizophrenic patients? Int. Clin. Psychopharmacol. 16, 1–19 (2001).

  43. 43.

    , & Risperidone (R64766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology 97, 206–212 (1989).

  44. 44.

    et al. Biochemical profile of risperidone, a new antipsychotic. J. Pharmacol. Exp. Ther. 247, 661–670 (1988).

  45. 45.

    , & Behavioral pharmacology of antagonists at 5-HT2/5-HT1C receptors. Neurosci. Biobehav. Rev. 16, 95–105 (1992).

  46. 46.

    , , & Behavioural and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rat. Psychopharmacology 86, 45–54 (1985).

  47. 47.

    , , , & Differential activation of Gq/11 and Gi(3) proteins at 5-hydroxytryptamine(2C) receptors revealed by antibody capture assays: influence of receptor reserve and relationship to agonist-directed trafficking. Mol. Pharmacol. 62, 578–589 (2002).

  48. 48.

    & Risperidone: a potential treatment for autism. Curr. Opin. Investig. Drugs 3, 1212–1216 (2002).

  49. 49.

    Pharmacology Training Group. The fall and rise of in vivo pharmacolog. Trends Pharmacol. Sci. 23, 13–18 (2002).

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Encyclopedia of Life Sciences

  1. Opiates

    • Janssen Pharmaceutica

      • 5-HT1A receptor

        • 5-HT2A receptor

          • dopamine D2 receptor

            Acknowledgements

            The author is grateful to Drs M. Kleven, P. Pauwels and A. Newman-Tancredi for their contribution on an earlier version of this paper.

            Author information

            Affiliations

            1. Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres Cédex, France. francis.colpaert@pierre-fabre.com

              • Francis C. Colpaert

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