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Corticosteroid sensitization drives opioid addiction

Molecular Psychiatry volume 27, pages 2492–2501 (2022)Cite this article

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Abstract

The global crisis of opioid overdose fatalities has led to an urgent search to discover the neurobiological mechanisms of opioid use disorder (OUD). A driving force for OUD is the dysphoric and emotionally painful state (hyperkatifeia) that is produced during acute and protracted opioid withdrawal. Here, we explored a mechanistic role for extrahypothalamic stress systems in driving opioid addiction. We found that glucocorticoid receptor (GR) antagonism with mifepristone reduced opioid addiction-like behaviors in rats and zebrafish of both sexes and decreased the firing of corticotropin-releasing factor neurons in the rat amygdala (i.e., a marker of brain stress system activation). In support of the hypothesized role of glucocorticoid transcriptional regulation of extrahypothalamic GRs in addiction-like behavior, an intra-amygdala infusion of an antisense oligonucleotide that blocked GR transcriptional activity reduced addiction-like behaviors. Finally, we identified transcriptional adaptations of GR signaling in the amygdala of humans with OUD. Thus, GRs, their coregulators, and downstream systems may represent viable therapeutic targets to treat the “stress side” of OUD.

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Fig. 1: Chronic glucocorticoid receptor antagonism blunts the development of heroin addiction-like behaviors.
Fig. 2: Chronic glucocorticoid receptor antagonism decreases the excitability of CeA CRF cells.
Fig. 3: Acute glucocorticoid receptor antagonism reverses escalated IV methadone self-administration.
Fig. 4: Increasing the SRC-1a isoform in the CeA reduces heroin self-administration in rats under LgA conditions.
Fig. 5: Transcriptional evidence of the activation of GR signaling in individuals with histories of opioid dependence.
Fig. 6: Glucocorticoid receptor-dependent plasticity in the CeA mediates opioid addiction-like behaviors.

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Acknowledgements

This study was supported by the NIDA Intramural Research Program. We thank the NIDA drug supply program and NIDA Intramural Research Program pharmacy for providing and dispensing heroin and methadone. Human tissue was obtained from the National Institutes of Health NeuroBioBank at the University of Miami Brain Endowment Bank and University of Pittsburgh Brain Tissue Donation Program. The authors thank Shiliang Zhang and Rong Ye from the NIDA Confocal and Electron Microscopy Core for their expert technical assistance, Lauren Brick from NIDA media for figure preparation, Brandon Harvey for providing PC12 cells, and Michael Arends for proofreading the manuscript. SAC, JCMV, MAM, JMB, CR, MM, GFK, and LFV were supported by the NIDA Intramural Research Program. ROM was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (AA026075). VRC received support from NIDA (DA048882). PPS received support from NIDA (DA043268). GDB received a Canadian Institutes of Health Research fellowship. Crh-Cre rats can be obtained from the Rat Resource and Research.

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Authors and Affiliations

  1. Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, Baltimore, MD, USA

    Stephanie A. Carmack, Janaina C. M. Vendruscolo, M. Adrienne McGinn, Jorge Miranda-Barrientos, Marisela Morales, George F. Koob & Leandro F. Vendruscolo

  2. Center for Adaptive Systems of Brain-Body Interactions, George Mason University, Fairfax, VA, USA

    Stephanie A. Carmack

  3. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA

    Vez Repunte-Canonigo, Yu Fu & Pietro P. Sanna

  4. Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA

    Gabriel D. Bosse & Randall T. Peterson

  5. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

    Daniele Mercatelli & Federico M. Giorgi

  6. Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    Anthony J. Hinrich, Francine M. Jodelka & Michelle L. Hastings

  7. Ionis Pharmaceuticals, Carlsbad, CA, USA

    Karen Ling & Frank Rigo

  8. Waggoner Center for Alcohol and Addiction Research, Department of Neuroscience and Neurology, University of Texas, Austin, TX, USA

    Robert O. Messing

  9. Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Scott Edwards

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  1. Stephanie A. Carmack
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Contributions

SAC, KL, ROM, RTP, FR, SE, PPS, MM, MLH, GFK and LFV designed the experiments. SAC, JCMV, MAM, JMB, VRC, GDB, AJH, and FMJ conducted the experiments. SAC, JCMV, MAM, JMB, VRC, GDB, DM, FMG, YF, AJH, FMJ, PPS, MLH and LFV performed the data analysis. SAC, GFK and LFV wrote the manuscript with the help of all authors.

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Correspondence to Leandro F. Vendruscolo.

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Carmack, S.A., Vendruscolo, J.C.M., Adrienne McGinn, M. et al. Corticosteroid sensitization drives opioid addiction. Mol Psychiatry 27, 2492–2501 (2022). https://doi.org/10.1038/s41380-022-01501-1

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