Effect of Transcutaneous Vagus Nerve Stimulation on Ketamine Reinstatement

초록

Despite growing concerns over ketamine addiction, the underlying mechanisms of relapse and effective therapeutic interventions remain poorly understood, especially in comparison to opioids and psychostimulants. Previous studies have demonstrated that vagus nerve stimulation (VNS) reduces relapse-like behaviors in animal models of cocaine and heroin addiction, and VNS is already used clinically to treat depression and epilepsy. In this study, we established a cue-induced reinstatement model of ketamine addiction in mice and evaluated the effects of transcutaneous VNS (tVNS) on relapse-related behaviors and neural activity across addiction-related brain regions. Using a self-administration paradigm followed by extinction and cue-induced reinstatement, behavioral analysis revealed a rapid decrease in active lever pressing during extinction, and a significant increase in drug-seeking behavior during reinstatement. c-Fos immunostaining revealed increased neuronal activity in the hippocampus, medial prefrontal cortex (mPFC), and central amygdala (CeA), suggesting their involvement in ketamine-induced relapse. Notably, tVNS-treated mice exhibited lower level of drug-seeking behavior compared to controls. These findings suggest that tVNS may attenuate ketamine craving and relapse by modulating neural excitability within key addiction-relevant circuits.