Abstract
Posttraumatic stress disorder (PTSD) is a debilitating trauma and stressor-related disorder that has become a major neuropsychiatric problem, leading to substantial disruptions in individual health and societal costs. Our previous studies have demonstrated that hypidone hydrochloride (YL-0919), a novel combined selective 5-HT reuptake inhibitor/5-HT1A receptor partial agonist/5-HT6 receptor full agonist, exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 exerts anti-PTSD effects and its underlying mechanisms are still unclear. In the present study, we showed that repeated treatment with YL-0919 caused significant suppression of contextual fear, enhanced anxiety and cognitive dysfunction induced by the time-dependent sensitization (TDS) procedure in rats and by inescapable electric foot-shock in a mouse model of PTSD. Furthermore, we found that repeated treatment with YL-0919 significantly reversed the accompanying decreased expression of the brain-derived neurotrophic factor (BDNF) and the synaptic proteins (synapsin1 and GluA1), and ameliorated the neuroplasticity disruption in the prefrontal cortex (PFC), including the dendritic complexity and spine density of pyramidal neurons. Taken together, the current study indicated that YL-0919 exerts clear anti-PTSD effects, which might be partially mediated by ameliorating the structural neuroplasticity by increasing the expression of BDNF and the formation of synaptic proteins in the PFC.
Highlights
Posttraumatic stress disorder (PTSD) is characterized by intrusive re-experiences of trauma-related events, sustained avoidance of stimuli related to traumatic events, negative changes in cognition and mood, exaggerated startle responses and hypervigilance according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5)
Post hoc analysis confirmed that treatment with YL-0919 (1.25, 2.5 mg/kg) significantly reversed the decrease in recognition index (RI) compared with vehicle treatment in the timedependent sensitization (TDS) rats (p < 0.05 and p < 0.01 for the dosages of 1.25 and 2.5, respectively)
We found that chronic YL-0919 treatment caused significant suppression in the contextual fear, enhanced anxiety and cognitive dysfunction induced by the inescapable electric foot-shock in a mouse model of PTSD and by the TDS procedure in rats
Summary
Posttraumatic stress disorder (PTSD) is characterized by intrusive re-experiences of trauma-related events, sustained avoidance of stimuli related to traumatic events, negative changes in cognition and mood, exaggerated startle responses and hypervigilance according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5). It is common that PTSD cooccurs with major depressive disorder, substance abuse and other anxiety disorders, and these comorbidity conditions will further worsen the severity of PTSD, leading to a high risk of a suicide attempt and causing substantial disruptions for the individual and in society (Sareen, 2014; Shalev et al, 2017). Only paroxetine and sertraline, two selective serotonin reuptake inhibitor (SSRI) antidepressants, have been approved by the Food and Drug Administration (FDA) as the first-line pharmacotherapeutic agents for the PTSD treatment.
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