Morphine reward in dopamine-deficient mice
Abstract
Dopamine has been widely implicated as a mediator of many of the behavioural responses to drugs of abuse. 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.
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Dopamine deficient mice can learn to associate place cues and the affective action of morphine, and if treated with caffeine or L-DOPA just before the performance phase, they display a preference for the compartment paired with morphine.
“Dopamine deficient mice can learn to associate place cues and the affective action of morphine, and if they are treated with caffeine or L-DOPA, which temporarily restores their dopamine, just before the performance phase, they display a preference for the compartment paired with morphine (Hnasko et al., 2005).”
From Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens–olfactory tubercle complex (2007) · cites this paper as Hnasko et al., 2005
Cites
Di Chiara, G., & Imperato, A. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.14.5274 · Cited by 4,733 · see citing works
What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?
Berridge, K. C., & Robinson, T. E. (1998) · Brain Research Reviews · doi:10.1016/s0165-0173(98)00019-8 · Cited by 4,127 · see citing works
Dopamine, learning and motivation.
Wise, R. A. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1406 · Cited by 3,379 · see citing works
Opioids excite dopamine neurons by hyperpolarization of local interneurons
Johnson, S., & North, R. (1992) · The Journal of Neuroscience · doi:10.1523/jneurosci.12-02-00483.1992 · Cited by 1,637 · see citing works
The dopamine hypothesis of reward: past and current status
Spanagel, R., & Weiss, F. (1999) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01447-2 · Cited by 967 · see citing works
Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic
Zhou, Q.-Y., & Palmiter, R. D. (1995) · Cell · doi:10.1016/0092-8674(95)90145-0 · Cited by 731 · see citing works
Self-citationPettit, H. O., Ettenberg, A., Bloom, F. E., & Koob, G. F. (1984) · Psychopharmacology · doi:10.1007/bf00427441 · Cited by 651 · see citing works
The role of the basal ganglia in nociception and pain
Chudler, E. H., & Dong, W. K. (1995) · Pain · doi:10.1016/0304-3959(94)00172-b · Cited by 601 · see citing works
Intracranial self-administration of morphine into the ventral tegmental area in rats
Bozarth, M. A., & Wise, R. A. (1981) · Life Sciences · doi:10.1016/0024-3205(81)90148-x · Cited by 503 · see citing works
Morphine-induced activation of A10 dopamine neurons in the rat
Gysling, K., & Wang, R. Y. (1983) · Brain Research · doi:10.1016/0006-8993(83)90913-7 · Cited by 493 · see citing works
Absence of opiate rewarding effects in mice lacking dopamine D2 receptors
Maldonado, R. J., Saiardi, A., Valverde, O., Samad, T. A., Roques, B. P., & Borrelli, E. (1997) · Nature · doi:10.1038/41567 · Cited by 431 · see citing works
Cannon, C. M., & Palmiter, R. D. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-34-10827.2003 · Cited by 280 · see citing works
Self-citationShippenberg, T. S., Bals-Kubik, R., & Herz, A. (1993) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)38109-7 · Cited by 275 · see citing works
The role of dopamine in the nucleus accumbens in analgesia
Altier, N., & Stewart, J. (1999) · Life Sciences · doi:10.1016/s0024-3205(99)00298-2 · Cited by 273 · see citing works
Reinforcing effects of morphine in the nucleus accumbens
OLDS, M. E. (1982) · Brain Research · doi:10.1016/0006-8993(82)90454-1 · Cited by 259 · see citing works
Distinguishing whether dopamine regulates liking, wanting, and/or learning about rewards
Robinson, S., Sandstrom, S. M., Denenberg, V. H., & Palmiter, R. D. (2005) · Behavioral Neuroscience · doi:10.1037/0735-7044.119.1.5 · Cited by 247 · see citing works
Self-citationFeeding behavior in dopamine-deficient mice
Szczypka, M. S., Rainey, M. A., Kim, D. S., Alaynick, W. A., Marck, B. T., Matsumoto, A. M., & Palmiter, R. D. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.21.12138 · Cited by 242 · see citing works
Self-citationBechara, A., & van der Kooy, D. (1989) · Journal of Neuroscience · doi:10.1523/jneurosci.09-10-03400.1989 · Cited by 204 · see citing works
Manzanedo, C., Aguilar, M. A., Rodríguez‐Arias, M., & Miñarro, J. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00164-4 · Cited by 139 · see citing works
Bozarth, M. A. (1987) · Brain Research · doi:10.1016/0006-8993(87)91327-8 · Cited by 133 · see citing works
Fenu, S., Bassareo, V., & Chiara, G. D. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-17-06897.2001 · Cited by 128 · see citing works
Murphy, N. P., Lam, H. A., & Maidment, N. T. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00599.x · Cited by 120 · see citing works
Elmer, G. I., Pieper, J. O., Rubinstein, M., Low, M. J., Grandy, D. K., & Wise, R. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-10-j0004.2002 · Cited by 94 · see citing works
A Two-Separate-Motivational-Systems Hypothesis of Opioid Addiction
Bechara, A. (1998) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(97)00047-6 · Cited by 87 · see citing works
Analgesia and Abuse Potential: An Accidental Association or a Common Substrate?
Franklin, K. B. J. (1998) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(97)00535-2 · Cited by 77 · see citing works
King, M. A., Bradshaw, S. L., Chang, A., Pintar, J. E., & Pasternak, G. W. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-19-07788.2001 · Cited by 73 · see citing works
Dockstader, C. L., Rubinstein, M., Grandy, D. K., Low, M. J., & van der Kooy, D. (2001) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2001.01455.x · Cited by 64 · see citing works
Heusner, C. L., Hnasko, T. S., Szczypka, M. S., Liu, Y., During, M. J., & Palmiter, R. D. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02986-x · Cited by 48 · see citing works
Kim, D. S., & Palmiter, R. D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252753799 · Cited by 47 · see citing works
Self-citation
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Koob, G. F., & Volkow, N. D. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.110 · Cited by 5,340 · see citing works
Reconsidering anhedonia in depression: Lessons from translational neuroscience
Treadway, M. T., & Zald, D. H. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.06.006 · Cited by 1,579 · see citing works
Ikemoto, S. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2007.05.004 · Cited by 1,477 · see citing works
Tzschentke, T. M. (2007) · Addiction Biology · doi:10.1111/j.1369-1600.2007.00070.x · Cited by 1,336 · see citing works
Affective neuroscience of pleasure: reward in humans and animals
Berridge, K. C., & Kringelbach, M. L. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1099-6 · Cited by 1,254 · see citing works
The Neuroscience of Drug Reward and Addiction
Volkow, N. D., Michaelides, M., & Baler, R. (2019) · Physiological Reviews · doi:10.1152/physrev.00014.2018 · Cited by 863 · see citing works
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Berridge, K. C. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.07990.x · Cited by 700 · see citing works
A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP
Lisman, J., Grace, A. A., & Duzel, E. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.07.006 · Cited by 465 · see citing works
Opponency revisited: competition and cooperation between dopamine and serotonin
Boureau, Y.-L., & Dayan, P. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.151 · Cited by 456 · see citing works
Zweifel, L. S., Parker, J. G., Lobb, C. J., Rainwater, A., Wall, V. Z., Fadok, J. P., Darvas, M., Kim, M. J., Mizumori, S. J. Y., Paladini, C. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813415106 · Cited by 426 · see citing works
Self-citationFields, H. L., & Margolis, E. B. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.01.002 · Cited by 432 · see citing works
Palmiter, R. D. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1417.003 · Cited by 375 · see citing works
Self-citationLand, B. B., Bruchas, M. R., Schattauer, S., Giardino, W. J., Aita, M., Messinger, D., Hnasko, T. S., Palmiter, R. D., & Chavkin, C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910705106 · Cited by 301 · see citing works
Self-citationNeurotransmitter Corelease: Mechanism and Physiological Role
Hnasko, T. S., & Edwards, R. H. (2012) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020911-153315 · Cited by 284 · see citing works
“However, mice can also learn CPP in the absence of dopamine (102, 103), and the cue-reward pairing involved in CPP occurs continuously over the course of 20 min and may therefore not depend on transient subsecond bursts in dopamine neuron firing.”
Self-citationCalculating utility: preclinical evidence for cost–benefit analysis by mesolimbic dopamine
Phillips, P. E. M., Walton, M. E., & Jhou, T. C. (2007) · Psychopharmacology · doi:10.1007/s00213-006-0626-6 · Cited by 237 · see citing works
Smith, R. J., & Aston-Jones, G. (2008) · Brain Structure and Function · doi:10.1007/s00429-008-0191-3 · Cited by 206 · see citing works
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Nummenmaa, L., & Tuominen, L. (2018) · British Journal of Pharmacology · doi:10.1111/bph.13812 · Cited by 178 · see citing works
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Liu, Y., Young, K. A., Curtis, J. T., Aragona, B. J., & Wang, Z. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.1006-11.2011 · Cited by 103 · see citing works
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Self-citationSkupio, U., Tertil, M., Bilecki, W., Barut, J., Korostynski, M., Golda, S., Kudla, L., Wiktorowska, L., Sowa, J. E., Siwiec, M., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-019-0450-4 · Cited by 36 · see citing works
- Authors
- Hnasko, T. S., Sotak, B. N., & Palmiter, R. D.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Palmiter, Richard D.
- Venue
- Nature
- Published
- 2005-12
- Volume
- 438
- Issue
- 7069
- Pages
- 854-857
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2033505470
- Cited by
- 338
- References
- 29
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 11 · 2023: 8 · 2022: 12 · 2021: 67 · 2020: 12 · 2019: 20 · 2018: 11 · 2017: 10 · 2016: 10 · 2015: 12 · 2014: 12 · 2013: 12 · 2012: 20
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- University of Washington
- National Institute on Drug Abuse
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- morphine reward, dopamine deficiency, conditioned place preference, morphine analgesia, tail-flick test, drug addiction, pleasure
- MeSH terms
- Analgesics, Opioid, Animals, Brain, Caffeine, Dihydroxyphenylalanine, Dopamine, Dose-Response Relationship, Drug, Levodopa, Morphine, Motor Activity, Pain, Reward, Tail, Tyrosine 3-Monooxygenase, Pain Threshold, Mice
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