Adjunct treatment with ketamine enhances the therapeutic effects of extinction learning after chronic unpredictable stress

Post-traumatic stress disorder (PTSD) is a debilitating illness characterized by dysfunction in the medial prefrontal cortex (mPFC). Although both pharmacological and cognitive behavioral interventions have shown some promise at alleviating symptoms, high attrition and persistence of treatment-resistant symptoms pose significant challenges that remain unresolved. Specifically, prolonged exposure therapy, a gold standard intervention to treat PTSD, has high dropout rates resulting in many patients receiving less than a fully effective course of treatment. Administering pharmacological treatments together with behavioral psychotherapies like prolonged exposure may offer an important avenue for enhancing therapeutic efficacy sooner, thus reducing the duration of treatment and mitigating the impact of attrition. In this study, using extinction learning as a rat model of exposure therapy, we hypothesized that administering ketamine as an adjunct treatment together with extinction will enhance the efficacy of extinction in reversing stress-induced deficits in set shifting, a measure of cognitive flexibility. Results showed that combining a sub-effective dose of ketamine with a shortened, sub-effective extinction protocol fully reversed stress-induced cognitive set-shifting deficits in both male and female rats. These effects may be due to shared molecular mechanisms between extinction and ketamine, such as increased neuronal plasticity in common circuitry (e.g., hippocampus-mPFC), or increased BDNF signaling. This work suggests that fast-acting drugs, such as ketamine, can be effectively used in combination with behavioral interventions to reduce treatment duration and potentially mitigate the impact of attrition. Future work is needed to delineate other pharmacotherapies that may complement the effects of extinction via shared or independent mechanisms.