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. 2020 Jun;237(6):1633-1642.
doi: 10.1007/s00213-020-05487-y. Epub 2020 Feb 24.

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

Aldemara I Silva  1 , Victor A D Holanda  1 , Joaquim G Azevedo Neto  1 , Edilson D Silva Junior  1 , Vanessa P Soares-Rachetti  1 , Girolamo Calo  2 , Chiara Ruzza  2 , Elaine C Gavioli  3
Affiliations

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

Aldemara I Silva et al. Psychopharmacology (Berl). 2020 Jun.

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.

Keywords: Anxiety; Depression; Helpless behavior; Inescapable stress; NOP antagonist; Nociceptin/orphanin FQ.

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