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Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning

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Abstract

Converging evidence suggests opioid abuse can increase the incidence and severity of post-traumatic stress disorder (PTSD) in clinical populations. Interestingly, opioid withdrawal alone can produce symptoms similar to those of PTSD. Despite this association, the neural mechanisms underlying the relationship of opioid abuse, withdrawal, and PTSD is poorly understood. Our laboratory has investigated the neurobiological underpinnings of stress-enhanced fear learning (SEFL), an animal model of PTSD-like symptoms. We have previously shown that, in SEFL, a severe footshock induces an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and subsequent fear learning is blocked by DH IL-1 receptor antagonism (IL-1RA). Given that opioids and stress engage similar neuroimmune mechanisms, the present experiments investigate whether the same mechanisms drive heroin withdrawal to induce a PTSD-like phenotype. First, we tested the effect of a chronic escalating heroin dose and withdrawal regimen on fear learning and found it produces enhanced future fear learning. Heroin withdrawal also induces a time-dependent, region-specific increase in IL-1β and glial fibrillary acidic protein (GFAP) immunoreactivity within the dentate gyrus of the DH. IL-1β was significantly colocalized with GFAP, indicating astrocytes may be involved in increased IL-1β. Moreover, intra-DH infusions of IL-1RA 0, 24, and 48 h into heroin withdrawal prevents the development of enhanced fear learning but does not alter withdrawal-induced weight loss. Collectively, our data suggests heroin withdrawal is sufficient to produce enhanced fear learning, astrocytes may play a role in heroin withdrawal-induced IL-1β, and DH IL-1 signaling during withdrawal mediates the development of heroin withdrawal–enhanced fear learning.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This research was supported by National Institute on Drug Abuse (NIDA) grants R01 DA034721 (DTL), T32 DA007244 (SVP, JEP, CLL), and F31 DA047054 (JEP); a National Science Foundation grant DGE-1144081 (CLL); a Richard A. King Research Excellence Award (SVP); and a Behavioral Neuroscience Graduate Student Opportunity Fund (SVP).

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Contributions

SVP led the conception, design, and conduction of experiments, data collection and analysis, and drafting, revision, and submission of the manuscript. DTL, JEP, and CLL significantly contributed to the design and conduction of experiments, data interpretation, and critical revisions of the manuscript.

Corresponding author

Correspondence to Donald T. Lysle.

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All procedures were conducted in accordance with federal guidelines and with approval from the University of North Carolina at Chapel Hill Institutional Animal Care and Use Committee.

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The authors declare that there is no conflict of interest.

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Parekh, S.V., Paniccia, J.E., Lebonville, C.L. et al. Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning. Psychopharmacology 237, 3653–3664 (2020). https://doi.org/10.1007/s00213-020-05645-2

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  • DOI: https://doi.org/10.1007/s00213-020-05645-2

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