• Author
    Hillary Nguyen
  • Discovery PI

    Ausaf A Bari

  • Project Co-Author

    Jacob A Alderete, Kaihan Danesh, Dylan Cavalheiro, Iman Habibagahi, Roshan P Matthews, Aydin Babakhani, Catherine M Cahill

  • Abstract Title

    Wireless Vagus Nerve Stimulation Prevents Relapse in a Rodent Model of Fentanyl Use Disorder

  • Discovery AOC Petal or Dual Degree Program

    Basic, Clinical, & Translational Research

  • Abstract

    Introduction

    Opioid use disorder (OUD) remains a national crisis, with fentanyl driving most overdose deaths. Current pharmacotherapies reduce craving but maintain dependence, highlighting the need for circuit-based interventions. Vagus nerve stimulation (VNS) modulates prefrontal-limbic networks involved in reward and stress regulation. Prior work using wired VNS reduced drug seeking in cue-induced relapse models with cocaine and heroin, but these paradigms poorly capture the stress-driven relapse common in OUD. Here, we tested whether wireless VNS delivered during extinction training confers lasting protection against stress-induced reinstatement in a fentanyl self-administration model, addressing both translational and methodological gaps in prior studies.


    Methods

    Eleven adult Sprague-Dawley rats underwent single-stage implantation of a left cervical VNS cuff and jugular catheter. After recovery, rats self-administered fentanyl (2 hr/day, 12 days) with a light cue signaling drug delivery. During extinction (no drug or cue), animals were randomized, balancing for average lever presses during training, to VNS (n = 5; 30 s trains every 5 min, 1.5 mA, 30 Hz) or sham (n = 6) groups. Extinction continued until active presses fell below 10/day. To model relapse, yohimbine was administered to induce stress-related reinstatement; no stimulation was delivered during this phase.

     

    Results

    Extinction rates did not differ between groups. A one-way ANOVA revealed a significant main effect of treatment on reinstatement lever pressing (F(3,18) = 7.89, p = 0.0014). Post-hoc Tukey’s multiple comparisons test showed significantly fewer active lever presses in the animals that previously received active left VNS compared to active left sham (p = 0.0050)

     

    Conclusion

    Wireless VNS during extinction reduced later stress-induced relapse, even without ongoing stimulation, suggesting durable plasticity within stress-reward circuits. While prior wired systems showed similar effects in cue-based models, this study is the first to demonstrate long-term relapse prevention using a stress paradigm and a fully wireless platform. These findings position VNS as a promising neuromodulatory adjunct for OUD, extending neuromodulation beyond movement disorders and mood applications.

     

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