Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Av. Sen. Salgado Filho, 3000, Lagoa Nova, Natal, 59078-970, Brazil.
Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
Psychopharmacology (Berl). 2020 Jun;237(6):1633-1642. doi: 10.1007/s00213-020-05487-y. Epub 2020 Feb 24.
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.
This study aimed to investigate the effects of the NOP antagonist SB-612111 on footshock stress-induced anxiety behaviors.
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.
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.
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.
抑郁和焦虑经常同时发生，这具有重要的临床意义。先前的研究表明，孤啡肽/N 端前体（NOP）受体的激活会产生抗焦虑作用，而其阻断则会促进一致的抗抑郁作用。NOP 拮抗剂在逆转足部电击引起的抑郁样行为方面是有效的，但它们对应激引起的焦虑的影响仍不清楚。
本研究旨在探讨 NOP 拮抗剂 SB-612111 对足部电击应激引起的焦虑行为的影响。
雄性瑞士小鼠暴露于无法逃避的电击应激中，根据逃避足部电击的能力（即无助或非无助）筛选行为表型。然后，用地西泮（1mg/kg）和 SB-612111（0.1-10mg/kg）治疗动物，并在高架十字迷宫（EPM）和旷场试验中评估它们的行为。
与未应激的小鼠相比，无助但非无助的动物在 EPM 中进入和停留在开放臂的时间明显减少。地西泮显著增加了无助、非无助和未应激小鼠进入开放臂的次数。然而，NOP 拮抗剂 SB-612111 在未处理的小鼠中没有活性，而在无助的小鼠中它逆转了与焦虑相关的行为，并增加了非无助小鼠的焦虑状态。未观察到对运动的影响。
无助的小鼠与未应激和非无助的动物相比表现出更高的焦虑，因此支持使用这种方法作为研究焦虑/抑郁共病的动物模型。此外，SB-612111 根据个体应激易感性调节雄性小鼠的焦虑样行为。最终，NOP 拮抗剂可能对治疗抑郁患者的焦虑有用。
