Abstract
A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene.
Highlights
Posttraumatic stress disorder (PTSD), induced by a single or repeated exposures to severe traumatic events and/or physiological stress, frequently lead to long-lasting debilitating illnesses (Gustavsson et al, 2011; Bisson et al, 2015)
By using an animal model of PTSD that consisted of 10 inescapable electric foot shocks (IFS), we investigated whether ketamine combined with extinction training may diminish anxiety-like behavior and facilitate persistent fear erasure in adult mice
Our study provides experimental evidence that the long-term (22 days) treatment with ketamine in combination with extinction training may produce the suppression of IFS-induced anxiety-like behavior and fear relapse in mice, and the effects were similar to those induced by Flx
Summary
Posttraumatic stress disorder (PTSD), induced by a single or repeated exposures to severe traumatic events and/or physiological stress, frequently lead to long-lasting debilitating illnesses (Gustavsson et al, 2011; Bisson et al, 2015). These disorders seriously undermine the mental health of the affected individuals, and impose an enormous public health and economic burden on society (Yehuda and LeDoux, 2007; Gustavsson et al, 2011). There is an urgent need in elucidation of the neurobiological mechanisms underlying alleviating effects of combination of pharmaco- and psychotherapies
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