AbstractObjectivesIn the study, we examined the effects of ketamine and extremely low‐frequency electromagnetic fields (ELF‐EMF) on depression‐like behavior, learning and memory, expression of GFAP, caspase‐3, p53, BDNF, and NMDA receptor in animals subjected to chronic unpredictable stress (CUS).MethodsAfter applying 21 days of chronic unpredictable stress, male rats received intraperitoneal (IP) of ketamine (5 mg/kg) and then were exposed to ELF‐EMF (10‐Hz, 10‐mT exposure conditions) for 3 days (3 h per day) and behavioral assessments were performed 24 h after the treatments. Instantly after the last behavioral test, the brain was extracted for Nissl staining, immunohistochemistry, and real‐time PCR analyses. Immunohistochemistry (IHC) was conducted to assess the effect of ketamine and ELF‐EMF on the expression of astrocyte marker (glial fibrillary acidic protein, GFAP) in the CA1 area of the hippocampus and medial prefrontal cortex (mPFC). Also, real‐time PCR analyses were used to investigate the impacts of the combination of ketamine and ELF‐EMF on the expression of caspase3, p53, BDNF, and NMDA receptors in the hippocampus in rats submitted to the CUS procedure. Results were considered statistically significant whenp< .05.ResultsOur results revealed that the combination of ketamine and ELF‐EMF increased depression‐like behavior, increased degenerated neurons and decreased the number of GFAP (+) cells in the CA1 area and mPFC, incremented the expression of caspase‐3, and reduced the expression of BDNF in the hippocampus but showed no effect on the expression of p53 and NMDA‐R.ConclusionsThese results reveal that combining ketamine and ELF‐EMF has adverse effects on animals under chronic unpredictable stress (CUS).