Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression
Open accessAbstract
A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.
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Blockade of glial cell activation restores mesolimbic dopamine function, prevents withdrawal, prevents relapse of morphine-seeking behavior, and prevents incubation-induced heroin seeking in rats.
“The blockade of glial cell activation restored mesolimbic dopamine function using minocycline (Taylor et al., 2016), prevented withdrawal using various inhibitors of glial cell activation (Watkins et al., 2009), prevented the relapse of morphine-seeking behavior via the epigenetic reprogramming of interleukin-10 overexpression (Schwarz et al., 2011), and prevented incubation-induced heroin seeking”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Schwarz et al., 2011
Maternal separation plus handling reduces CpG island methylation of Il10 in microglia isolated from the NAc of adult male rats, a change absent in whole tissue.
“Similar to these findings that suggest there is an increased pro-inflammatory phenotype in offspring exposed to ELS, the anti-inflammatory cytokine Il10 showed reduced levels of CpG island methylation in microglia isolated from the NAc of adult male rats that underwent MS as well as handling, a change that was absent in whole tissue from the NAc [131].”
From Cell-type-specific epigenetic effects of early life stress on the brain (2022) · cites this paper as [131]
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References 59 · Cited by 203
- Authors
- Schwarz, J. M., Hutchinson, M. R., & Bilbo, S. D.
- Affiliations
- Duke University (US)
- The University of Adelaide (AU)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-12-07
- Volume
- 31
- Issue
- 49
- Pages
- 17835-17847
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3259856
- OpenAlex
- W1974684238
- Cited by
- 203
- References
- 59
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 13 · 2023: 11 · 2022: 13 · 2021: 13 · 2020: 15 · 2019: 12 · 2018: 12 · 2017: 26 · 2016: 8 · 2015: 22 · 2014: 14 · 2013: 21 · 2012: 8
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- Australian Research Council (DP110100297)
- National Health and Medical Research Council (465423)
- National Institute on Drug Abuse (R01DA025978, F32DA030136)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- morphine, conditioned place preference, reinstatement of drug seeking, microglial activation, IL-10, epigenetic methylation, neonatal handling, maternal care, nucleus accumbens, ibudilast, glial activation, gene-environment interaction, opioid use disorder, anti-inflammatory cytokines
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Chromatography, Liquid, Conditioning, Operant, Corticosterone, Extinction, Psychological, Female, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Handling, Psychological, Life Change Events, Male, Microinjections, Morphine, Naloxone, Narcotic Antagonists, Narcotics, Nucleus Accumbens, Reinforcement, Psychology, Mass Spectrometry, Interleukin-10, Rats, Sprague-Dawley, Microglia, CD11b Antigen, Immunoprecipitation, Rats, Epigenomics, Drug-Seeking Behavior
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