Abstract
Incubation of craving is a well-documented phenomenon referring to the intensification of drug craving over extended abstinence. The neural adaptations that occur during forced abstinence following chronic drug taking have been a topic of intense study. However, little is known about the transcriptomic changes occurring throughout this window of time. To define gene expression changes associated with morphine consumption and extended abstinence, male and female rats underwent 10 days of morphine self-administration. Separate drug-naive rats self-administered sucrose in order to compare opioid-induced changes from those associated with natural, non-drug rewards. After one or 30 days of forced abstinence, rats were tested for craving, or nucleus accumbens shell tissue was dissected for RNA sequencing. Morphine consumption was predictive of drug seeking after extended (30 days) but not brief (1 day) abstinence in both sexes. Extended abstinence was also associated with robust sex- and reinforcer-specific changes in gene expression, suggesting sex differences underlying incubation of morphine and sucrose seeking respectively. Importantly, these changes in gene expression occurred without re-exposure to drug-paired cues, indicating that chronic morphine causes long-lasting changes in gene expression that prime the system for increased craving. These findings lay the groundwork for identifying specific therapeutic targets for curbing opioid craving without impacting the natural reward system in males and females.
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Acknowledgements
We thank the NIDA drug supply for gifting the morphine sulfate used in these studies. We would also like to thank Shivam Bhakta, Rachel Carpenter, and Kyle Peer for their technical assistance, as well as iGEM NGS-Prep Laboratory at Temple University for use of their bioanalyzer. This research includes calculations carried out on Temple University’s HPC resources and thus was supported in part by the National Science Foundation through major research instrumentation grant number 1625061 and by the US Army Research Laboratory under contract number W911NF-16-2-0189
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This work was supported by the National Institutes of Health grant NIH/NIDA DP1 DA046537, K01 DA039308 (MEW), and T32 DA007237 (CCB and ABT; Unterwald EM, PI).
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HLM, CCB and MEW designed the studies. HLM, CCB, RK, DRP, ARB, ASE, ABT and SHD contributed to data collection and data analysis. HLM, CCB and MEW drafted the manuscript. All authors edited and approved manuscript.
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Mayberry, H.L., Bavley, C.C., Karbalaei, R. et al. Transcriptomics in the nucleus accumbens shell reveal sex- and reinforcer-specific signatures associated with morphine and sucrose craving. Neuropsychopharmacol. 47, 1764–1775 (2022). https://doi.org/10.1038/s41386-022-01289-2
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DOI: https://doi.org/10.1038/s41386-022-01289-2
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