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Early social isolation stress increases addiction vulnerability to heroin and alters c-Fos expression in the mesocorticolimbic system

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Abstract

Rationale

Adverse psychosocial factors during early childhood or adolescence compromise neural structure and brain function, inducing susceptibility for many psychiatric disorders such as substance use disorder. Nevertheless, the mechanisms underlying early life stress-induced addiction vulnerability is still unclear, especially for opioids.

Objectives

To address this, we used a mouse heroin self-administration model to examine how chronic early social isolation (ESI) stress (5 weeks, beginning at weaning) affects the behavioral and neural responses to heroin during adulthood.

Results

We found that ESI stress did not alter the acquisition for sucrose or heroin self-administration, nor change the motivation for sucrose on a progressive ratio schedule. However, ESI stress induced an upward shift of heroin dose-response curve in female mice and increased motivation and seeking for heroin in both sexes. Furthermore, we examined the neuronal activity (measured by c-Fos expression) within the key brain regions of the mesocorticolimbic system, including the prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc) core and shell, caudate putamen, and ventral tegmental area (VTA). We found that ESI stress dampened c-Fos expression in the PrL, IL, and VTA after 14-day forced abstinence, while augmented the neuronal responses to heroin-predictive context and cue in the IL and NAc core. Moreover, ESI stress disrupted the association between c-Fos expression and attempted infusions during heroin-seeking test in the PrL.

Conclusions

These data indicate that ESI stress leads to increased seeking and motivation for heroin, and this may be associated with distinct changes in neuronal activities in different subregions of the mesocorticolimbic system.

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Acknowledgements

We thank Dr. David Dietz (State University of New York at Buffalo) for his feedback on experimental design. We also thank Dr. Adam Smith and Dr. Jai Subramanian (University of Kansas) for technical support.

Funding

This study was supported by University of Kansas start-up funding and the National Institutes of Health National Institute on Drug Abuse (Grant Number K01DA050908 to Z.-J. W.).

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  1. Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS, 66045, USA

    Archana Singh, Yang Xie, Ashton Davis & Zi-Jun Wang

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  1. Archana Singh
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  2. Yang Xie
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A.S. performed experiments, analyzed data, and wrote part of the Methods; Y. X. performed experiments and analyzed data; A. D. performed experiments; and Z.-J. W. designed experiments, performed experiments, supervised the project, and wrote the manuscript.

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Correspondence to Zi-Jun Wang.

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Singh, A., Xie, Y., Davis, A. et al. Early social isolation stress increases addiction vulnerability to heroin and alters c-Fos expression in the mesocorticolimbic system. Psychopharmacology 239, 1081–1095 (2022). https://doi.org/10.1007/s00213-021-06024-1

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