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.

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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.

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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.

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Correspondence to Richard D. Palmiter.

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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)

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

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