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Rewarding effects of opiates are absent in mice lacking the receptor for substance P

Nature volume 405, pages 180183 (11 May 2000) | Download Citation

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Abstract

Modulation of substance P activity offers a radical new approach to the management of depression, anxiety and stress1,2,3. The substance P receptor is highly expressed in areas of the brain that are implicated in these behaviours, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards such as food and of drugs of abuse such as opiates4,5,6,7. Here we show a loss of the rewarding properties of morphine in mice with a genetic disruption of the substance P receptor. The loss was specific to morphine, as both groups of mice responded when cocaine or food were used as rewards. The physical response to opiate withdrawal was also reduced in substance P receptor knockout mice. We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse.

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References

  1. 1.

    et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392, 394–397 (1998).

  2. 2.

    et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 1640–1645 (1998).

  3. 3.

    , , & Effect of tachykinin receptor inhibition in the brain on cardiovascular and behavioural responses to stress. J. Pharmacol. Exp. Ther. 280, 238–246 (1997).

  4. 4.

    et al. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J. Comp. Neurol. 347, 249–274 (1994).

  5. 5.

    Neurobiology of addiction. Curr. Opin. Neurobiol. 6 , 243–251 (1996).

  6. 6.

    & Drug addiction: bad habits add up. Nature 398, 567–570 (1999).

  7. 7.

    , & Neuroscience of addiction. Neuron 21, 467–476 (1998).

  8. 8.

    & Drug abuse: Hedonic homeostatic dysregulation. Science 278, 52– 70 (1997).

  9. 9.

    Substance P (neurokinin-I) receptor mRNA is selectively expressed in cholinergic neurons in the striatum and basal forebrain. Brain Res. 556, 165–170 (1991).

  10. 10.

    et al. Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388, 586– 589 (1995).

  11. 11.

    et al. Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377, 424– 428 (1995).

  12. 12.

    & A psychomotor stimulant theory of addiction. Psychol. Rev. 97, 469– 492 (1987).

  13. 13.

    & A single brain stem substrate mediates the motivational effects of both opiates and food in nondeprived rats but not in deprived rats. Behav. Neurosci. 106 , 351–363 (1992).

  14. 14.

    , & RP 67580, a selective antagonist of neurokinin-1 receptors, modifies some of the naloxone-precipitated morphine withdrawal signs in rats. Neurosci. Lett. 156, 135– 140 (1993).

  15. 15.

    et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the m-opioid-receptor gene. Nature 383, 819–823 (1996).

  16. 16.

    et al. A Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology (in the press).

  17. 17.

    , , & Role of different brain structures in the expression of the physical morphine withdrawal syndrome. J. Pharmacol. Exp. Ther. 261, 669– 677 (1992).

  18. 18.

    Physical dependence produced by central morphine infusions: an anatomical mapping study. Neurosci. Biobehav. Rev. 18, 373–383 (1994).

  19. 19.

    , , , & Immunohistochemical localization of the cloned mu opioid receptor in the rat CNS. J. Chem. Neuroanat. 8, 283–305 (1995).

  20. 20.

    , , & The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl Acad. Sci. USA 89, 12048–12052 (1992).

  21. 21.

    , & Differential regulation of adenylyl cyclase activity by mu and delta opioids in rat caudate putamen and nucleus accumbens. J. Pharmacol. Exp. Ther. 267, 145– 152 (1993).

  22. 22.

    & Induction of chronic Fos-related antigens in rat brain by chronic morphine administration. Mol. Pharmacol. 49, 636–645 ( 1996).

  23. 23.

    et al. Expression of the transcription factor delta FosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

  24. 24.

    , , , & Coexpression of dopamine D2 and substance P (neurokinin-1) receptor messenger RNAs by a subpopulation of cholinergic neurons in the rat striatum. Neuroscience 53, 417–424 (1993).

  25. 25.

    , , & The basal ganglia and adaptive motor control. Science 265, 1826–1831 (1994).

  26. 26.

    & Behavioural effects of tachykinins and related peptides. Brain Res. 381, 68–76 (1986).

  27. 27.

    , , , & Relationship between dopamine release in nucleus accumbens and place preference induced by substance P injected into the nucleus basalis magnocellularis region. Neuroscience 64, 1054–1055 (1995).

  28. 28.

    & Stress reinstates heroin-seeking in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacol. 119, 334–341 (1995).

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Acknowledgements

We thank J. O'Brien, J. A. Perez De Gracia, and P. Mantyh, R. Maldonado and C. Stanford for reading and commenting on the manuscript, and N. Rupriak for sharing unpublished data.

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  1. *Instituto de Neurosciencias, Universidad Miguel Hernandez, Ap. correos 18, 03550 Alicante, Spain

    • Patricia Murtra
    •  & Carmen De Felipe
  2. †Department of Anatomy and Developmental Biology, University College London, Medawar Building, Gower Street, London WC1E 6BT, UK

    • Anne M. Sheasby
    •  & Stephen P. Hunt

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Correspondence to Stephen P. Hunt.

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https://doi.org/10.1038/35012069

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