Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice
Open accessAbstract
Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain's response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1β signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1β can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects - enhanced local inhibition via a switch in IL-1β signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1β in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1β may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA-approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuroimmune-based treatments for AUD.
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Glutamatergic and GABAergic signaling in the ILC contributes to inhibitory control over alcohol seeking and relapse.
“Additionally, glutamatergic and GABAergic signaling in the ILC contributes to inhibitory control over alcohol seeking and relapse (29, 34–37).”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [37]
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Self-citation
Flagged first, then by citations
3 of the 106 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Bajo M, Patel RR, Hedges DM, Varodayan FP, Vlkolinsky R, Davis TD, Burkart MD, Blednov YA, Roberto M, 2019b. Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala. Brain Sci 9. 10.3390/brainsci9120361 PMC6956324 31817854 · DOI
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- Authors
- Varodayan, F. P., Pahng, A. R., Davis, T. D., Gandhi, P., Bajo, M., Steinman, M. Q., Kiosses, W. B., Blednov, Y. A., Burkart, M. D., Edwards, S., Roberts, A. J., & Roberto, M.
- Affiliations
- Scripps Research Institute (US)
- Southeast Louisiana Veterans Health Care System (US)
- Binghamton University (US)
- La Jolla Institute for Immunology (US)
- The University of Texas at Austin (US)
- University of California San Diego (US)
- Louisiana State University Health Sciences Center New Orleans (US)
- Corresponding author
- Roberto, M.
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 110
- Pages
- 125-139
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC10106421
- OpenAlex
- W4322627124
- Cited by
- 50
- References
- 106
- Citations by year
- 2026: 17 · 2025: 15 · 2024: 8 · 2023: 10
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 307 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Brain Behavior and Immunity (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AA007456, AA-017823, AA017447, AA006420, AA027700, 5r37aa017447-15)
- National Institute on Alcohol Abuse and Alcoholism (R37-AA017447, R01AA021491, R01AA025996, R00AA025408, P50AA006420, R01AA027700, K99AA025408, R01AA017447, U01AA013498, R01AA029841, U01AA013520, T32AA007456, P50AA017823, P60AA006420)
- National Institute of General Medical Sciences (K99GM129454, R00GM129454)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- chronic ethanol exposure, IL-1β, neuroinflammation, GABAergic synapses, medial prefrontal cortex, prelimbic cortex, alcoholism, ethanol dependence, MyD88 signaling, p38 MAPK, PI3K/Akt signaling, inhibitory synapses, pyramidal neurons, neuroimmune signaling, interleukin-1 receptor antagonist
- MeSH terms
- Ethanol, Alcoholism, Animals, Male, Mice, Inbred C57BL, Prefrontal Cortex, Phosphatidylinositol 3-Kinases, p38 Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, Mice, Interleukin-1beta, Myeloid Differentiation Factor 88
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