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Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

Emilia M. Lefevre, Marc T. Pisansky, Carlee Toddes, Federico Baruffaldi, Marco Pravetoni, Lin Tian, Thomas J. Y. Kono, Patrick E. Rothwell
doi: https://doi.org/10.1101/646356
Emilia M. Lefevre
1Department of Neuroscience, University of Minnesota, Minneapolis, MN
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Marc T. Pisansky
1Department of Neuroscience, University of Minnesota, Minneapolis, MN
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Carlee Toddes
2Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN
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Federico Baruffaldi
3Hennepin Healthcare Research Institute, Minneapolis, MN
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Marco Pravetoni
3Hennepin Healthcare Research Institute, Minneapolis, MN
6Center for Immunology, University of Minnesota, Minneapolis, MN
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Lin Tian
7Department of Biochemistry and Molecular Medicine, University of California, Davis, CA
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Thomas J. Y. Kono
8Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN
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Patrick E. Rothwell
1Department of Neuroscience, University of Minnesota, Minneapolis, MN
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  • For correspondence: rothwell@umn.edu
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ABSTRACT

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may therefore represent a strategy to minimize iatrogenic effects on brain reward circuits.

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Posted February 13, 2020.
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Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System
Emilia M. Lefevre, Marc T. Pisansky, Carlee Toddes, Federico Baruffaldi, Marco Pravetoni, Lin Tian, Thomas J. Y. Kono, Patrick E. Rothwell
bioRxiv 646356; doi: https://doi.org/10.1101/646356
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Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System
Emilia M. Lefevre, Marc T. Pisansky, Carlee Toddes, Federico Baruffaldi, Marco Pravetoni, Lin Tian, Thomas J. Y. Kono, Patrick E. Rothwell
bioRxiv 646356; doi: https://doi.org/10.1101/646356

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