Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats

•One VNS train decreases anxiety in rats submitted to the elevated plus maze.•Five VNS trains promote anxiolytic effects in rats submitted to different anxiety tests.•Acute VNS does not decrease baseline startle response.•Anxiolytic effects of VNS could be useful to increase tolerability in exposure-based therapies. Chronic vagus nerve stimulation (VNS) attenuates anxiety in rats and humans. However, it is unclear whether VNS can promote acute anxiolytic effects. Here we examined short-term anxiolytic effects of VNS using single or multiple trains in rats submitted to a battery of tests. Three groups of rats were implanted with VNS cuffs and tested for anxiety using the elevated plus maze (EPM), novelty suppressed feeding (NSF), and acoustic startle response (ASR), after receiving either one or five VNS trains (0.4 mA/30 Hz/30‑sec), or sham stimulation. Both single and multiple VNS trains reduced state anxiety as measured using the EPM, but only multiple trains reduced anxiety in the EPM and NSF. VNS did not decrease arousal as measured using the ASR. The anxiolytic effects of VNS may be differently influenced by test order or prior-exposure to stress. VNS did not affect startle responses in naïve rats but the present findings do not determine whether VNS would affect startle responses that are potentiated by fear or anxiety. A single VNS train can produce an anxiolytic-like effect in the EPM minutes later, an effect that is not observed in the NSF. Delivering 5 VNS trains restores the immediate effects across tests of anxiety, indicating that more trains produce a more robust anxiolytic effect. The lack of effects on ASR suggests that VNS affects state anxiety but not baseline arousal in naïve rats. We suggest that the anxiolytic effect of VNS can increase tolerability and reduce dropout in exposure-based therapies.