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Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2

Neuropsychopharmacologyvolume 43pages19241933 (2018) | Download Citation

Abstract

Psychosocial stress contributes to the development of psychiatric disorders. Repeated social defeat (RSD) is a murine stressor that causes a release of inflammatory monocytes into circulation. Moreover, RSD-induced anxiety-like behavior is dependent on the recruitment of these monocytes to the brain. Activation of the endocannabinoid (ECB) system may modulate both neuroendocrine and inflammatory responses mediated by stress. Therefore, we hypothesized that a cannabinoid receptor agonist would attenuate RSD-induced inflammation, anxiety, and stress sensitization. To test this hypothesis, mice received an injection of the synthetic cannabinoid1/2 receptor agonist, WIN55,212-2 (WIN; 1 mg/kg, intraperitoneally) daily for six consecutive days, 30 min before each exposure to RSD. Anxiety-like behavior, immune activation, neuroinflammation, and microglial reactivity were determined 14 h after RSD. RSD-induced anxiety-like behavior in the open field and in the EPM was reversed by WIN55,212-2. Moreover, WIN55,212-2 reduced the accumulation of inflammatory monocytes in circulation and brain after RSD and attenuated RSD-induced interleukin-1β (IL-1β) messenger RNA (mRNA) expression in microglia/macrophages. Increased ex vivo reactivity of microglia/monocytes to lipopolysaccharides (LPS) after RSD was also attenuated by WIN55,212-2. Next, fear expression, extinction, and recall were evaluated 24 and 48 h, respectively, after contextual fear conditioning, which took place 7 days after RSD. Here, RSD caused prolonged fear expression and impaired fear extinction recall, which was associated with increased IL-1β mRNA in the brain. Moreover, these stress-induced effects were reversed by WIN55,212-2. In conclusion, activation of cannabinoid receptors limited the immune and neuroinflammatory responses to RSD and reversed the short-term and long-term behavioral deficits associated with RSD.

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Acknowledgements

We thank David Hammond, Daniel Shea, Yufen Wang, and Brooke Benner (Ohio State University) for the excellent technical support. This work was support by FAPESP (2014/212260-0 to SFL, 2012/17626-7 to FSG and SFL) and NIH (R01-MH-093473 and R01-MH-093472 to JFS). All authors report no biomedical financial interests or potential conflicts of interest.

Author information

Affiliations

  1. Department of Pharmacology, University of Sao Paulo (USP), Ribeirão Preto, São Paulo, 14049900, Brazil

    • Sabrina Francesca Lisboa
    • , Leonardo Barbosa Resstel
    •  & Francisco Silveira Guimaraes
  2. Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Medical School of Ribeirão Preto, University of Sao Paulo (USP), Ribeirão Preto, São Paulo, 14049900, Brazil

    • Sabrina Francesca Lisboa
    • , Leonardo Barbosa Resstel
    •  & Francisco Silveira Guimaraes
  3. Division of Biosciences, Ohio State University, Columbus, OH, 43210, USA

    • Anzela Niraula
    • , Jonathan P. Godbout
    •  & John F. Sheridan
  4. Department of Neuroscience, Ohio State University, Columbus, OH, 43210, USA

    • Jonathan P. Godbout
    •  & John F. Sheridan
  5. Center for Brain and Spinal Cord Repair, Ohio State University, Columbus, OH, 43210, USA

    • Jonathan P. Godbout
  6. Institute for Behavioral Medicine Research, Ohio State University, Columbus, OH, 43210, USA

    • John F. Sheridan

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The authors declare no competing interests.

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Correspondence to Sabrina Francesca Lisboa.

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https://doi.org/10.1038/s41386-018-0064-2