Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Acute Vagus Nerve Stimulation Facilitates Short Term Memory and Cognitive Flexibility in Rats.

Vagus nerve stimulation (VNS) causes the release of several neuromodulators, leading to cortical activation and deactivation. The resulting preparatory cortical plasticity can be used to increase learning and memory in both rats and humans. The effects of VNS on cognition have mostly been studied either in animal models of different pathologies, and/or after extended VNS. Considerably less is known about the effects of acute VNS. Here, we examined the effects of acute VNS on short-term memory and cognitive flexibility in naïve rats, using three cognitive tasks that require comparatively brief (single session) training periods. In all tasks, VNS was delivered immediately before or during the testing phase. We used a rule-shifting task to test cognitive flexibility, a novel object recognition task to measure short-term object memory, and a delayed spontaneous alternation task to measure spatial short-term memory. We also analyzed exploratory behavior in an elevated plus maze to determine the effects of acute VNS on anxiety. Our results indicate that acute VNS can improve memory and cognitive flexibility relative to Sham-stimulation, and these effects are independent of unspecific VNS-induced changes in locomotion or anxiety.

Vagus nerve stimulation during extinction learning reduces conditioned place preference and context-induced reinstatement of cocaine seeking.

BACKGROUND: Drug use causes the formation of strong cue/reward associations which persist long after cessation of drug-taking and contribute to the long-term risk of relapse. Extinguishing these associations may reduce cue-induced craving and relapse. Previously, we found that pairing vagus nerve stimulation (VNS) with extinction of cocaine self-administration reduces cue-induced reinstatement; however, it remains unclear whether this was primarily caused by extinguishing the context, the instrumental response, or both. OBJECTIVE: Hypothesis: We hypothesized that VNS can facilitate the extinction of both contextual cues and instrumental responding. METHODS: Extinction of context was first tested using Pavlovian conditioned place preference (CPP). Next, the impact of VNS on the extinction of instrumental responding was assessed under ABA and AAA context conditions. In each extinction context separate groups of rats were either provided the opportunity to perform the instrumental response, or the levers were retracted for the duration of extinction training. Reinstatement was induced by reintroduction of the conditioned stimuli and/or the drug-paired context. Data were analyzed using one-way or two-way repeated measures ANOVAs. RESULTS: VNS during extinction reduced reinstatement of CPP. VNS also reduced cue- and context-induced reinstatement of the instrumental response under both AAA and ABA conditions. The subjects' ability to engage with the lever during extinction was crucial for this effect. P values < 0.05 were considered significant. CONCLUSIONS: Craving occurs in response to a range of conditioned stimuli and contexts; VNS may improve outcomes of behavioral therapy by facilitating extinction of both an instrumental response and/or contextual cues.