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Alterations in brain activation in response to prolonged morphine withdrawal-induced behavioral inflexibility in rats

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Abstract

Rationale

The inability to stop a repetitive maladaptive behavior is a main problem in addictive disorders. Neuroadaptations that are associated with behavioral inflexibility may be involved in compulsive drug use.

Objectives

The aim of the present study was to investigate the pattern of behavioral inflexibility during morphine withdrawal and map brain activation that is linked to alterations in flexibility.

Methods

We first analyzed the effects of chronic morphine exposure on reversal learning after 2-week (short-term) and 6-week (prolonged) morphine withdrawal. We then compared the level of neuronal activation using cFos immunohistochemistry in 15 brain areas between rats that underwent morphine withdrawal and saline-control rats after a test of reversal learning.

Results

Only prolonged morphine withdrawal impaired reversal learning. Rats that exhibited impairments in reversal learning presented a significant decrease in cFos expression in the orbitofrontal cortex (OFC), including the medial, lateral, and ventral OFC. cFos expression significantly increased in the dorsomedial striatum and major subregions of the medial prefrontal cortex (mPFC) in the morphine group. Rats that underwent prolonged morphine withdrawal exhibited no significant changes in cFos expression in the dorsolateral striatum, nucleus accumbens, amygdala, paraventricular thalamic nucleus, or motor cortex. The rats that underwent short-term withdrawal did not present any changes in cFos expression in any of these brain regions.

Conclusion

Altogether, these data suggest that alterations in the function of the frontal cortex and its striatal connections during the late morphine withdrawal phase may underlie the disruption of inhibitory control in opioid dependence.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (31271098, 31571108), the National Key Basic Research Program of China (2015CB553501), and Beijing Natural Science Foundation (5162023).

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Author notes

  1. Chengji Piao and Tiane Liu contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China

    Chengji Piao, Tiane Liu, Lian Ma, Xuekun Ding, Xingyue Wang, Xing Chen, Ying Duan, Nan Sui & Jing Liang

  2. Department of Psychology, University of Chinese Academy of Sciences, Beijing, China

    Chengji Piao, Tiane Liu, Lian Ma, Xuekun Ding, Xingyue Wang, Xing Chen, Ying Duan, Nan Sui & Jing Liang

  3. Sino-Danish Center for Education and Research, Beijing, China

    Chengji Piao

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  1. Chengji Piao
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Contributions

Chengji Piao, Tiane Liu, Lian Ma, Xuekun Ding, and Xing Chen performed experiments. Chengji Piao, Tiane Liu, and Xingyue Wang analyzed data. Ying Duan assisted experiments. Nan Sui and Jing Liang designed the study. Chenji Piao and Jing Liang wrote the manuscript, and Jing Liang finalized the manuscript. All authors contributed to and have approved the final manuscript and agreed to be accountable for all aspects of the work.

Corresponding authors

Correspondence to Nan Sui or Jing Liang.

Ethics declarations

The experimental procedures were approved by the Institutional Review Board of the Institute of Psychology, Chinese Academy of Sciences and were in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Piao, C., Liu, T., Ma, L. et al. Alterations in brain activation in response to prolonged morphine withdrawal-induced behavioral inflexibility in rats. Psychopharmacology 234, 2941–2953 (2017). https://doi.org/10.1007/s00213-017-4689-3

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  • DOI: https://doi.org/10.1007/s00213-017-4689-3

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