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Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist

Nature volume 400, pages 371–375 (1999)Cite this article

Abstract

Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers1,2,3,4. In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction5,6,7. Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction3. Converging pharmacological8,9, human post-mortem10 and genetic11 studies implicate the dopamine D3 receptor12 in drug addiction. Here we have designed BP 897, the first D3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D3-receptor genes. BP 897 is a partial agonist in vitro and acts in vivo as either an agonist or an antagonist. We show that BP 897 inhibits cocaine-seeking behaviour that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects. Our data indicate that compounds like BP 897 could be used for reducing the drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli.

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Figure 1: BP 897 is a potent and partial D3 receptor agonist and a weak D2 receptor antagonist.
Figure 2: Agonistic effects of BP 897 on rotations in 6-OHDA-lesioned rats.
Figure 3: Antagonistic effects of BP 897 on c-fos gene expression in the islands of Calleja.
Figure 4: BP 897 inhibits cue-controlled cocaine-seeking but has no reinforcing effects.

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Acknowledgements

We thank C. Pilon for technical assistance and S. Fuchs, W. Rostene and C. Betancur for providing the D3-receptor-deficient mice. The work was supported by a Biomed II Programme grant to P.S., C.G.W. and B.J.E., a National Institute on Drug Abuse grant to P.S. and C.G.W. and an MRC Programme grant to B.J.E.

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Author notes

  1. Fabrice Garrido, André Mann and Camille G. Wermuth: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Psychology, University of Cambridge, Downing Street, CB2 3EB, Cambridge, UK

    Maria Pilla & Sylvie Perachon

  2. Unité de Neurobiologie et Pharmacologie Moléculaire, INSERM U 109, Centre Paul Broca, 2ter rue d'Alésia, 75014, Paris, France

    Maria Pilla & Barry J. Everitt

  3. Laboratoire Bioprojet, 9 rue Rameau, 75002, Paris, France

    Sylvie Perachon, FranÇois Sautel, Jean-Charles Schwartz & Pierre Sokoloff

  4. Laboratoire de Pharmacochimie de la Communication Cellulaire CNRS ERS 655, Faculté de Pharmacie, 74 route du Rhin BP 24, 67401, Illkirsch, France

    Sylvie Perachon

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Correspondence to Barry J. Everitt or Pierre Sokoloff.

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Pilla, M., Perachon, S., Sautel, F. et al. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature 400, 371–375 (1999). https://doi.org/10.1038/22560

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