Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Morphine reward in dopamine-deficient mice

Abstract

Dopamine has been widely implicated as a mediator of many of the behavioural responses to drugs of abuse1. To test the hypothesis that dopamine is an essential mediator of various opiate-induced responses, we administered morphine to mice unable to synthesize dopamine. We found that dopamine-deficient mice are unable to mount a normal locomotor response to morphine, but a small dopamine-independent increase in locomotion remains. Dopamine-deficient mice have a rightward shift in the dose–response curve to morphine on the tail-flick test (a pain sensitivity assay), suggesting either a decreased sensitivity to the analgesic effects of morphine and/or basal hyperalgesia. In contrast, dopamine-deficient mice display a robust conditioned place preference for morphine when given either caffeine or l-dihydroxyphenylalanine (a dopamine precursor that restores dopamine throughout the brain) during the testing phases. Together, these data demonstrate that dopamine is a crucial component of morphine-induced locomotion, dopamine may contribute to morphine analgesia, but that dopamine is not required for morphine-induced reward as measured by conditioned place preference.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Locomotor responses to morphine in dopamine-deficient and control mice.
Figure 2: Latencies to tail-flick by dopamine-deficient and control mice.
Figure 3: Conditioned place preference in dopamine-deficient and control mice.

Similar content being viewed by others

References

  1. Spanagel, R. & Weiss, F. The dopamine hypothesis of reward: past and current status. Trends Neurosci. 22, 521–527 (1999)

    Article  CAS  PubMed  Google Scholar 

  2. Wise, R. A. Dopamine, learning and motivation. Nature Rev. Neurosci. 5, 483–494 (2004)

    Article  CAS  Google Scholar 

  3. Berridge, K. C. & Robinson, T. E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28, 309–369 (1998)

    Article  CAS  PubMed  Google Scholar 

  4. Gysling, K. & Wang, R. Y. Morphine-induced activation of A10 dopamine neurons in the rat. Brain Res. 277, 119–127 (1983)

    Article  CAS  PubMed  Google Scholar 

  5. Di Chiara, G. & Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl Acad. Sci. USA 85, 5274–5278 (1988)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Shippenberg, T. S., Bals-Kubik, R. & Herz, A. Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors. J. Pharmacol. Exp. Ther. 265, 53–59 (1993)

    CAS  PubMed  Google Scholar 

  7. Manzanedo, C., Aguilar, M. A., Rodriguez-Arias, M. & Minarro, J. Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice. Behav. Brain Res. 121, 189–197 (2001)

    Article  CAS  PubMed  Google Scholar 

  8. Pettit, H. O., Ettenberg, A., Bloom, F. E. & Koob, G. F. Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology (Berl.) 84, 167–173 (1984)

    Article  CAS  Google Scholar 

  9. Bechara, A., Nader, K. & van der Kooy, D. A two-separate-motivational-systems hypothesis of opioid addiction. Pharmacol. Biochem. Behav. 59, 1–17 (1998)

    Article  CAS  PubMed  Google Scholar 

  10. Johnson, S. W. & North, R. A. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 12, 483–488 (1992)

    Article  CAS  PubMed  Google Scholar 

  11. Bozarth, M. A. Neuroanatomical boundaries of the reward-relevant opiate-receptor field in the ventral tegmental area as mapped by the conditioned place preference method in rats. Brain Res. 414, 77–84 (1987)

    Article  CAS  PubMed  Google Scholar 

  12. Bozarth, M. A. & Wise, R. A. Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sci. 28, 551–555 (1981)

    Article  CAS  PubMed  Google Scholar 

  13. Maldonado, R. et al. Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388, 586–589 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Elmer, G. I. et al. Failure of intravenous morphine to serve as an effective instrumental reinforcer in dopamine D2 receptor knock-out mice. J. Neurosci. 22, RC224 (2002)

    Article  PubMed  Google Scholar 

  15. Dockstader, C. L., Rubinstein, M., Grandy, D. K., Low, M. J. & van der Kooy, D. The D2 receptor is critical in mediating opiate motivation only in opiate-dependent and withdrawn mice. Eur. J. Neurosci. 13, 995–1001 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Zhou, Q. Y. & Palmiter, R. D. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83, 1197–1209 (1995)

    Article  CAS  PubMed  Google Scholar 

  17. Szczypka, M. S. et al. Feeding behaviour in dopamine-deficient mice. Proc. Natl Acad. Sci. USA 96, 12138–12143 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Murphy, N. P., Lam, H. A. & Maidment, N. T. A comparison of morphine-induced locomotor activity and mesolimbic dopamine release in C57BL6, 129Sv and DBA2 mice. J. Neurochem. 79, 626–635 (2001)

    Article  CAS  PubMed  Google Scholar 

  19. Heusner, C. L. et al. Viral restoration of dopamine to the nucleus accumbens is sufficient to induce a locomotor response to amphetamine. Brain Res. 980, 266–274 (2003)

    Article  CAS  PubMed  Google Scholar 

  20. Kim, D. S. & Palmiter, R. D. Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice. Proc. Natl Acad. Sci. USA 100, 1346–1351 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Chudler, E. H. & Dong, W. K. The role of the basal ganglia in nociception and pain. Pain 60, 3–38 (1995)

    Article  CAS  PubMed  Google Scholar 

  22. Franklin, K. B. Analgesia and abuse potential: an accidental association or a common substrate? Pharmacol. Biochem. Behav. 59, 993–1002 (1998)

    Article  CAS  PubMed  Google Scholar 

  23. Altier, N. & Stewart, J. The role of dopamine in the nucleus accumbens in analgesia. Life Sci. 65, 2269–2287 (1999)

    Article  CAS  PubMed  Google Scholar 

  24. King, M. A., Bradshaw, S., Chang, A. H., Pintar, J. E. & Pasternak, G. W. Potentiation of opioid analgesia in dopamine2 receptor knock-out mice: evidence for a tonically active anti-opioid system. J. Neurosci. 21, 7788–7792 (2001)

    Article  CAS  PubMed  Google Scholar 

  25. Cannon, C. M. & Palmiter, R. D. Reward without dopamine. J. Neurosci. 23, 10827–10831 (2003)

    Article  CAS  PubMed  Google Scholar 

  26. Robinson, S., Sandstrom, S. M., Denenberg, V. H. & Palmiter, R. D. Distinguishing whether dopamine regulates liking, wanting, and/or learning about rewards. Behav. Neurosci. 119, 5–15 (2005)

    Article  CAS  PubMed  Google Scholar 

  27. Bechara, A. & van der Kooy, D. The tegmental pedunculopontine nucleus: a brain-stem output of the limbic system critical for the conditioned place preferences produced by morphine and amphetamine. J. Neurosci. 9, 3400–3409 (1989)

    Article  CAS  PubMed  Google Scholar 

  28. Olds, M. E. Reinforcing effects of morphine in the nucleus accumbens. Brain Res. 237, 429–440 (1982)

    Article  CAS  PubMed  Google Scholar 

  29. Fenu, S., Bassareo, V. & Di Chiara, G. A role for dopamine D1 receptors of the nucleus accumbens shell in conditioned taste aversion learning. J. Neurosci. 21, 6897–6904 (2001)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank our colleagues F. Perez for help generating mice, and E. Kremer for providing us with virus used for Supplementary Fig. 2. We thank the University of Washington NIDA center program for use of Noldus software. We thank our colleagues C. Chavkin, W. Watt and S. Luquet for comments on the manuscript. T.S.H. was supported in part by a grant from NIGMS.Author Contributions The mouse model was developed in the R.D.P. laboratory. These experiments were designed and executed by T.S.H. with input from R.D.P. and assistance from B.N.S. for experiments shown in Fig. 1b and Supplementary Fig. 1.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard D. Palmiter.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Morphine (25 mg/kg) locomotor responses after caffeine (15 mg/kg) pre-treatment. (PDF 21 kb)

Supplementary Figure 2

CPP for morphine in vrDD and control mice. (PDF 15 kb)

Supplementary Figure Legends

Text to accompany the above Supplementary Figures. (DOC 21 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hnasko, T., Sotak, B. & Palmiter, R. Morphine reward in dopamine-deficient mice. Nature 438, 854–857 (2005). https://doi.org/10.1038/nature04172

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04172

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing