Pharmacotherapy and cognitive behavioral therapy, both fail to treat post-traumatic stress disorder (PTSD) in a considerable number of populations. The persistence of traumatic memories and deficit in extinction contributes to the failure of exposure therapy in PTSD. With the objective to enhance the outcomes of exposure therapy by targeting the extinction window using pharmacological agents in PTSD, the present study was aimed to explore the effect of piracetam, risperidone and their combinations in experimentally-induced PTSD-like phenotype in rats. Male SD rats were exposed to single prolonged stress model (SPS) for induction of PTSD-like behavioral changes. Piracetam, risperidone and their combination were used as therapeutic interventions while sertraline was used as a standard treatment for 14 days along with extinction training. Induction of PTSD-like behaviors were assessed in behavioral tests such as fear conditioning, elevated plus maze, social interaction test, and the marble burying test. Neurotransmitters (dopamine and serotonin and their metabolites), BDNF, proinflammatory cytokines (TNF-α, IL-6), caspase-3, and markers for oxidative stress were assessed in the hippocampus and cortex while corticosterone and nitrite levels were estimated in plasma. Our result indicated that the SPS paradigm efficiently induced PTSD-like phenotype in rats. Risperidone and piracetam were found to be effective alone, while their high dose combination, produced potentiating effect in reversing the extinction deficit, behavioral alterations, altered cortical and hippocampal BDNF, IL-6, TNF-α, caspase-3, oxidative stress markers, and neurotransmitter levels. Plasma corticosterone and nitrite levels were also found to be reversed in the combination treated groups. Our preliminary study suggests that piracetam, risperidone and their combination restored the physiological cascades in cortex and hippocampus along with successful suppression of fear memory and a symptom cluster of PTSD-like phenotype in rats. Hence they could be used as an effective adjunct to enhance the outcome of exposure therapy for the management of PTSD.
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