Sigma-1 receptor activation ameliorates anxiety-like behavior through NR2A-CREB-BDNF signaling pathway in a rat model submitted to single-prolonged stress

Accumulating evidence has demonstrated that the sigma-1 receptor (sigma-1R) possesses neuroprotective effects and is a potential novel therapeutic target for certain psychiatric diseases, including post-traumatic stress disorder (PTSD) accompanied with anxiety disorder. It has been reported that sigma-1R agonist treatment could be modulated by the brain-derived neurotrophic factor (BDNF) signaling pathway. However, it remains unclear whether BDNF and its upstream regulator are mechanistically involved in the therapeutic effect of sigma-1R in PTSD. To address this question, rats were subjected to a single-prolonged stress (SPS) paradigm and sigma-1R agonist administration. Open-field and elevated plus maze tests were implemented to evaluate the effect of sigma-1R activation on the improvement of anxiety-like behaviors. Furthermore, the expression levels of BDNF, phosphorylated cAMP responsive element-binding protein (CREB) and glutamate receptor ionotropic N-methyl D-aspartate 2A (NMDAR2A) were investigated in the hippocampi of rats. It was revealed that the downregulation of BDNF, phosphorylated CREB and NMDAR2A induced by SPS were reversed by sigma-1R activation. Collectively, the results of the present study suggest that the NMDAR2A/CREB/BDNF signaling pathway is involved in the activation of sigma-1R resulting in therapeutic effects for PTSD.