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Blockade of NOP receptor modulates anxiety-related behaviors in mice exposed to inescapable stress

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Abstract

Rationale

Depression and anxiety frequently co-occur, and this has important clinical implications. Previous studies showed that activation of the nociceptin/orphanin FQ receptor (NOP) elicits anxiolytic effects, while its blockade promotes consistent antidepressant actions. NOP antagonists are effective in reversing footshock-induced depressive-like behaviors, but their effects on stress-induced anxiety are still unclear.

Objective

This study aimed to investigate the effects of the NOP antagonist SB-612111 on footshock stress-induced anxiety behaviors.

Methods

Male Swiss mice were exposed to inescapable electric footshock stress, and behavioral phenotype was screened based on the ability to escape from footshock (i.e., helpless or non-helpless). Animals were then treated with diazepam (1 mg/kg) and SB-612111 (0.1–10 mg/kg), and their behavior was assessed in the elevated plus-maze (EPM) and open field test.

Results

When compared with non-stressed mice, helpless, but not non-helpless, animals displayed significant reductions in the time spent in and entries into open arms in the EPM. Diazepam significantly increased open arms exploration in helpless, non-helpless, and non-stressed mice. However, treatment with the NOP antagonist SB-612111 was inactive in naive mice, while it reversed anxiogenic-related behaviors in helpless mice and increased anxiety states in non-helpless mice. No effects on locomotion were observed.

Conclusion

Helpless mice displayed increased anxiety compared to non-stressed and non-helpless animals, thus supporting use of this approach as an animal model to investigate anxiety/depression comorbidity. Additionally, SB-612111 modulated anxiety-like behaviors in male mice depending on individual stress susceptibility. Ultimately, NOP antagonists could be useful for treating anxiety in depressed patients.

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Acknowledgments

AIS was recipient of MSc scholarship from the CAPES Foundation. VADH held a PDJ fellowship from Brazilian National Research Council.

Funding

This work was supported by funds from the Brazilian National Council Research (CNPq; Grant No. 302302/2015-8 and No. 401837/2016-5 to ECG).

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Authors and Affiliations

  1. Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Av. Sen. Salgado Filho, 3000, Lagoa Nova, Natal, 59078-970, Brazil

    Aldemara I. Silva, Victor A.D. Holanda, Joaquim G. Azevedo Neto, Edilson D. Silva Junior, Vanessa P. Soares-Rachetti & Elaine C. Gavioli

  2. Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy

    Girolamo Calo & Chiara Ruzza

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  1. Aldemara I. Silva
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  2. Victor A.D. Holanda
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Silva, A.I., Holanda, V.A., Azevedo Neto, J.G. et al. Blockade of NOP receptor modulates anxiety-related behaviors in mice exposed to inescapable stress. Psychopharmacology 237, 1633–1642 (2020). https://doi.org/10.1007/s00213-020-05487-y

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