Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drugseeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug-and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects.Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in networks that regulate motivated behavior (Moussawi et al. 2009). As a result of this, recovery from drug addiction is frequently hampered by craving and relapse. Learning to inhibit, or extinguish, drug-seeking in response to drug-associated cues can reduce relapse. Extinction can reverse neuroadaptations caused by drug self-administration (Self et al. 2004;Millan et al. 2011). However, extinction training alone is often insufficient to prevent drug relapse (Weiss et al. 2001;Conklin and Tiffany 2002), potentially because the corticolimbic networks that are important for cue and reward processing, which include the nucleus accumbens, the prefrontal cortex (PFC), and the amygdala (Jentsch and Taylor 1999), become dysregulated by chronic drug use themselves (Fowler et al. 2007;Sinha and Li 2007;Liu et al. 2009;Nic Dhonnchadha and Kantak 2011). Modulating extinction processes to better consolidate the new-formed memories thus has clinical potential to reshape maladaptive behavior and to prevent relapse (Taylor et al. 2009). Vagus nerve stimulation (VNS) is a minimally invasive neuroprosthetic treatment which can induce targeted plasticity in active networks (Hays et al. 2013). VNS is FDA-approved for the treatment of epilepsy and depression, and it can improve sensory and motor function in models of tinnitus and stroke (Engineer et al. 2011;Porter et al. 2012; Hays et al. 2014a,b). VNS has also already been shown ...