Time‐Dependent Therapeutic Effect of S ‐Ketamine on PTSD Mediated by VTA‐OFC Dopaminergic Neurocircuit

Early administration of S-Ketamine (on day 1) after trauma significantly improves PTSD symptoms in rodent models, particularly impaired fear extinction, while late administration (day 7) does not. The firing and burst rates of dopamine neurons in the ventral tegmental area (VTA) decrease after PTSD modeling and are restored only by early S-Ketamine. These VTA dopamine neurons respond to conditioned stimuli and help replace aversive memory encoding during fear extinction. Inhibiting the VTA-to-orbitofrontal cortex (OFC) pathway blocks S-Ketamine's therapeutic effect. A non-invasive brain stimulation targeting the OFC sensitizes cortical dopaminergic transmission and extends the effective time window of S-Ketamine for anti-PTSD treatment.

Study at a glance

Abstract

Current pharmacotherapies for post-traumatic stress disorder (PTSD) are limited by delayed onset and side effects. Despite ketamine exhibiting rapid relief of the core symptoms of PTSD, its clinical efficacy varies considerably depending on the timing of drug delivery. However, the underlying mechanism remains unclear. In this study, the therapeutic effects of early (day 1) and late (day 7) administration of S-Ketamine on behavioral phenotypes in rodent's models of PTSD are compared. It is observed that early rather than late administration of S-Ketamine significantly ameliorates PTSD symptoms, especially impaired fear extinction. The firing and burst rates of VTADA neurons consecutively decrease following PTSD modeling and are restored by early S-Ketamine intervention. In particular, VTADA neurons respond to the conditioned stimuli, mediating the replacement of aversive memory encoding during fear extinction. The inhibition of VTADA-OFC interrupts the PTSD treatment induced by S-Ketamine. A non-invasive temporally interfering brain stimulation targeting the OFC is further developed, sensitizing cortical dopaminergic transmission and extending the effective time window of S-Ketamine for anti-PTSD. Overall, a neural mechanism for the heterogeneous VTADA-OFC neurocircuit-mediated time-dependent therapeutic effect of S-Ketamine is illustrated. In addition, a novel technique is developed to optimize the strategy of ketamine-assisted psychotherapy for PTSD treatment.