Coelho Arthur A, Vila-Verde Carla, Sartim Ariandra G, Uliana Daniela L, Braga Laura A, Guimarães Francisco S, Lisboa Sabrina F
Pharmacology Department, Ribeirão Preto Medical School-University of São Paulo, São Paulo, Brazil.
Biomolecular Sciences Department, School of Pharmaceutical Sciences of Ribeirão Preto-University of São Paulo, São Paulo, Brazil.
Front Psychiatry. 2022 Jul 14;13:923177. doi: 10.3389/fpsyt.2022.923177. eCollection 2022.
Stress exposure can result in several proinflammatory alterations in the brain, including overexpression of the inducible isoform of nitric oxide synthase (iNOS) in the medial prefrontal cortex (mPFC). These changes may be involved in the development of many psychiatric conditions. However, it is unknown if iNOS in mPFC plays a significant role in stress-induced behavioral changes. The endocannabinoid (ECB) system is also influenced by stress. Its activation seems to be a counter regulatory mechanism to prevent or decrease the stress-mediated neuroinflammatory consequences. However, it is unclear if the ECB system and iNOS interact to influence stress consequences. This study aimed to test the hypothesis that the anti-stress effect of iNOS inhibition in mPFC involves the local ECB system, particularly the CB cannabinoid receptors. Male Wistar rats with guide cannula aimed at the mPFC were submitted to acute restraint stress (RS) for 2 h. In the following morning, rats received bilateral microinjections of vehicle, AM251 (CB antagonist; 100 pmol), and/or 1400W (iNOS selective inhibitor; 10, 10, or 10 nmol) into the prelimbic area of mPFC (PL-mPFC) before being tested in the elevated plus-maze (EPM). iNOS inhibition by 1400W prevented the anxiogenic-like effect observed in animals submitted to RS. The drug did not promote behavior changes in naive animals, demonstrating a stress-dependent effect. The 1400W-anti-stress effect was prevented by local pretreatment with AM251. Our data suggest that iNOS inhibition may facilitate the local endocannabinoid signaling, attenuating stress effects.
应激暴露可导致大脑出现多种促炎改变，包括内侧前额叶皮质（mPFC）中诱导型一氧化氮合酶（iNOS）的诱导型异构体过度表达。这些变化可能与许多精神疾病的发生有关。然而，mPFC中的iNOS是否在应激诱导的行为变化中起重要作用尚不清楚。内源性大麻素（ECB）系统也受应激影响。其激活似乎是一种反调节机制，以预防或减少应激介导的神经炎症后果。然而，尚不清楚ECB系统与iNOS是否相互作用以影响应激后果。本研究旨在验证以下假设：mPFC中iNOS抑制的抗应激作用涉及局部ECB系统，尤其是CB大麻素受体。将带有导向套管并指向mPFC的雄性Wistar大鼠进行2小时的急性束缚应激（RS）。在接下来的早晨，大鼠在高架十字迷宫（EPM）中接受测试之前，在mPFC的前边缘区（PL-mPFC）接受双侧微量注射溶剂、AM251（CB拮抗剂；100 pmol）和/或1400W（iNOS选择性抑制剂；10、10或10 nmol）。1400W抑制iNOS可预防RS大鼠中观察到的焦虑样效应。该药物未促进未经历应激的动物出现行为变化，表明其具有应激依赖性效应。局部用AM251预处理可阻止1400W的抗应激作用。我们的数据表明，iNOS抑制可能促进局部内源性大麻素信号传导，减轻应激效应。
