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Long-term impact of acute restraint stress on heroin self-administration, reinstatement, and stress reactivity

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Abstract

Rationale

There is a robust relationship between anxiety disorders, including post-traumatic stress disorder (PTSD) and substance abuse. In fact, 30–50% of people seeking treatment for substance abuse have a comorbid diagnosis for PTSD. Heroin use is at epic proportions in the USA and is commonly used by people with co-occurring PTSD symptoms and substance use disorder.

Objectives

Here, we combined animal assays of acute restraint stress and contingent heroin self-administration (SA) to study comorbidity between stress disorders and opioid use disorder and identify shifts in anxiety-like behaviors following stress and/or heroin in response to a stress-conditioned cue. Our objective for this approach was to determine the long-term impact of acute restraint stress and heroin self-administration on stress reactivity and basic reward processes.

Methods

We used 2-h acute restraint stress paired with an odor stimulus to condition a stress cue (CS) for testing of subsequent stress reactivity in a burying task and reinstatement and extinction to heroin seeking. Rats were also tested for social place preference for measures of social reward and anxiety-like behaviors.

Results

Stress rats exhibited multiple levels of disrupted behavior including enhanced acquisition of heroin intake and reinstatement in response to the stress CS, as well as delayed extinction in response to the stress CS. All rats developed a social place preference, but stress rats spent more time in nose-to-nose contact with the unfamiliar rat while heroin rats spent time exploring the chamber. In the burying task, stress shortened latencies to bury the CS and increased burying and immobility in male and female rats relative to sham counterparts.

Conclusions

Acute restraint stress results in anxiety-like behaviors and a stress-associated cue is sufficient to reinstate extinguished heroin seeking. This project has the potential to elucidate the complex relationship between stress/anxiety disorders, including some PTSD-like characteristics, and the onset, maintenance, and relapse to heroin seeking.

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Acknowledgments

We thank Jordan L. Hopkins for technical assistance. Heroin was supplied by the National Institute on Drug Abuse.

Funding

The data collected for this manuscript were supported by the National Institute of Health, National Institute on Drug Abuse grants: P50 DA016511 (CMR), U54 DA016511 (CMR, PWK), T32 DA728823 (RW), and College of Charleston Honors College Summer Enrichment Grant (JSC) and R25 DA033680 (JSC).

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Authors and Affiliations

  1. Department of Neuroscience, Medical University of South Carolina, Suite 416b BSB, MSC 510, 173 Ashley Ave, Charleston, SC, 29425, USA

    Jordan S. Carter, Angela M. Kearns, Kelsey M. Vollmer, Constanza Garcia-Keller, Rachel A. Weber, Nathaniel L. Baker, Peter W. Kalivas & Carmela M. Reichel

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  1. Jordan S. Carter
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  2. Angela M. Kearns
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  3. Kelsey M. Vollmer
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  4. Constanza Garcia-Keller
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  5. Rachel A. Weber
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  6. Nathaniel L. Baker
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  7. Peter W. Kalivas
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  8. Carmela M. Reichel
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Contributions

All authors discussed the experimental design, results, and implications at length. JSC, AMK, KMV, and RMW conducted the experiments including the stress protocol, surgery, and behavior. CGK supervised the stress exposure. JSC, KMV, and CMR contributed to writing the initial version of the manuscript and all authors edited the initial version. NLB and CRM conducted the statistical analysis. CMR wrote the final version of the manuscript. CGK, PWK, and CMR edited the final manuscript version.

Corresponding author

Correspondence to Carmela M. Reichel.

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Conflict of Interest

The authors declare that they have no conflicts of interests. Heroin was supplied by the NIDA drug supply program. This work was conducted in a facility constructed with support from NIDA C06RR015455.

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Carter, J.S., Kearns, A.M., Vollmer, K.M. et al. Long-term impact of acute restraint stress on heroin self-administration, reinstatement, and stress reactivity. Psychopharmacology 237, 1709–1721 (2020). https://doi.org/10.1007/s00213-020-05486-z

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  • DOI: https://doi.org/10.1007/s00213-020-05486-z

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