Anxiogenesis induced by social defeat in male mice: Role of nitric oxide, NMDA, and CRF1 receptors in the medial prefrontal cortex and BNST

• Published in: Neuropharmacology 2020-04, Vol.166, p.107973, Article 107973
• Main Authors: Faria, M.P., Laverde, C.F., Nunes-de-Souza, R.L.
• Format: Article
• Language: English
• Subjects: Anxiety; FosB + nNOS double-labeling; mPFC and BNST; Nitric oxide; NMDA and CRF1 receptors; Socially defeated mice
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.107973

Nitric oxide (NO) release in the right medial prefrontal cortex (RmPFC) produces anxiogenesis. In the bed nucleus of the stria terminalis (BNST), a region that receives neuronal projections from the mPFC, NO provokes anxiety, an effect that is blocked by local injections of corticotrophin-releasing factor type 1 receptor (CRF1) or n-methyl-d-aspartate receptor (NMDAr) antagonist. Anxiety is also enhanced by social defeat stress, and chronic stress impairs and facilitates, respectively, PFC and BNST roles in modulating behavioral responses to aversive situations. This study investigated whether the (i) chronic social defeat stress (CSDS) increases NO signaling in the mPFC; and/or (ii) anxiogenic effects provoked by the intra-RmPFC injection of NOC-9 (an NO donor) or by CSDS are prevented by intra-BNST injections of AP-7 (0.05 nmol) or CP 376395 (3.0 nmol), respectively, NMDAr and CRF1 antagonists, in male Swiss-Webster mice exposed to the elevated plus-maze (EPM). Results showed that (a) CSDS increased anxiety (i.e., reduced open-arm exploration) and repeatedly activated nNOS-containing neurons, as measured by ΔFosB (a stable nonspecific marker of neural activity) + nNOS double-labeling, in the right (but not left) mPFC, (b) NOC-9 in the RmPFC also increased anxiety, and (c) both CSDS and NOC-9 effects were reversed by injections of AP-7 or CP 376395 into the BNST. These results suggest that NMDA and CRF1 receptors located in BNST play an important role in the modulation of anxiety provoked by NO in the RmPFC, as well as by chronic social defeat in mice. •Nitric oxide (NO) in the right medial prefrontal cortex (RmPFC) induces anxiety.•Chronic social defeat stress (CSDS) provokes anxiety in mice.•CSDS also activates nNOS containing neurons in the RmPFC.•CRF1 or NMDA receptor blockade in the BNST prevents NO-induced anxiety in the RmPFC.•Both CRF1 and NMDA located in the BNST modulate social defeat anxiety.