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Higher anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid self-administration in rats

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Abstract

Rationale

Understanding factors contributing to individual differences in vulnerability to opioid addiction is essential for developing more effective preventions and treatments, yet few reliable behavioral predictors of subsequent opioid self-administration have been identified in rodents. Sensitivity to the acute effects of initial drug exposure predicts later addiction vulnerability in both humans and animals, but the relationship between sensitivity to withdrawal from initial drug exposure and later drug use vulnerability is unclear.

Objective

The goal of the current study was to evaluate whether the degree of anhedonia experienced during withdrawal from early opioid exposure predicts subsequent vulnerability to opioid self-administration.

Methods

Rats were first tested for withdrawal sensitivity following acute injections of morphine (i.e., “acute dependence”), measured as elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during naloxone-precipitated and spontaneous withdrawal. Rats were then tested for addiction-like behavior using various measures of i.v. morphine self-administration (MSA) including acquisition, demand, extinction, and reinstatement induced by morphine, stress, and/or drug-associated cues.

Results

Greater naloxone-precipitated withdrawal across repeated morphine injections and greater peak spontaneous withdrawal severity following a single morphine injection were associated with lower addiction-like behavior on multiple MSA measures. Withdrawal-induced anhedonia predicted a wider range of MSA measures than did any individual measure of MSA itself.

Conclusions

Our data establish WIA as one of the first behavioral measures to predict individual differences in opioid SA in rodents. This model promises to be useful for furthering our understanding of behavioral and neurobiological mechanisms underlying vulnerability to opioid addiction.

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Acknowledgments

The authors thank Mary Krueger, Joseph Tombers, Haley Rudnick, and Nettie Enshayan for their excellent technical assistance.

Funding

Supported by NIH/NIDA grant R21 DA037728 (Gewirtz/Harris, Co-PIs), the Hennepin Healthcare Research Institute (formerly Minneapolis Medical Research Foundation) Translational Addiction Research Program (Harris PI), a Hennepin Healthcare Research Institute Career Development Award for PhD Investigators (Harris PI), and NIDA training grant T32 DA007097 (Swain, Y; Molitor T, PI).

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Authors and Affiliations

  1. Hennepin Healthcare Research Institute, 701 Park Avenue, Minneapolis, MN, 55415, USA

    Yayi Swain, Peter Muelken, Annika Skansberg, Danielle Lanzdorf, Zachary Haave, Mark G. LeSage & Andrew C. Harris

  2. Department of Psychology, University of Minnesota, Minneapolis, MN, USA

    Yayi Swain, Annika Skansberg, Danielle Lanzdorf, Mark G. LeSage, Jonathan C. Gewirtz & Andrew C. Harris

  3. Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA

    Zachary Haave & Jonathan C. Gewirtz

  4. Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    Mark G. LeSage & Andrew C. Harris

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  1. Yayi Swain
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Correspondence to Andrew C. Harris.

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All procedures were approved by The Institutional Animal Care and Use Committee (IACUC) of the Hennepin Health Research Institute in accordance with the 2011 NIH Guide for the Care and Use of Laboratory Animals and the 2003 National Research Council Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research.

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Swain, Y., Muelken, P., Skansberg, A. et al. Higher anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid self-administration in rats. Psychopharmacology 237, 2279–2291 (2020). https://doi.org/10.1007/s00213-020-05532-w

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