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September 10, 2025

Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation

Key Points

Vagus nerve stimulation significantly enhances the firing activity of norepinephrine neurons, and subsequently serotonin neurons.
Neuron firing patterns change drastically, with increased spontaneous firing rates and burst firing observed after VNS.
Lesioning norepinephrine neurons abolishes the increased firing rate of serotonin neurons, indicating an interdependence between these neurotransmitters.
The activation of postsynaptic receptors in serotonin neurons improves after VNS, linking it to antidepressant efficacy in treatment-resistant depression.

Abstract

Background: Vagus nerve stimulation (VNS) is a recent intervention for treatment-resistant depression. Electrophysiological recordings in the rat brain showed that VNS increases the firing rate of norepinephrine (NE) neurons after 1 day of stimulation and that of serotonin (5-HT) neurons after 14 days. This study was conducted to further characterize these effects. Methods: We implanted rats with a VNS electrode and stimulator. We used the selective noradrenergic toxin DSP-4 to lesion NE neurons of the locus coeruleus. We recorded dorsal raphe 5-HT neurons under chloral hydrate anesthesia. We recorded hippocampus CA 3 pyramidal neurons using 5-barreled iontophoretic pipettes. Results: Analysis of a previously published data set revealed that VNS increased not only the spontaneous firing rates of NE neurons, but also the percentage of neurons firing in bursts. The enhancement of the 5-HT neuron firing rate by VNS was abolished by lesioning NE neurons. We found that VNS increased the degree of activation of postsynaptic α 1 -adrenoceptors on 5-HT neurons, probably through an increased release of endogenous NE. The tonic activation of postsynaptic 5-HT 1A receptors in the hippocampus was enhanced after 14 days of VNS, as with other antidepressant treatments. Limitations: Our study limitations include the fact that we turned off the stimulator during the electrophysiological recordings, which likely decreased the vagal tone to the brain. Also, we obtained the data while the animals were under anesthesia, therefore studies need to be carried out in unanesthetized rats to ascertain whether the anesthetic agent influenced the changes observed between control rats and those treated with VNS. Conclusion: Vagus nerve stimulation initially increases the firing activity and pattern of NE neurons and subsequently those of 5-HT neurons, presumably as a cascade effect via α 1 -postsynaptic adrenoceptors. To date, VNS appears to be a unique antidepressant treatment increasing 5-HT transmission and enhancing the firing activity of NE neurons. These effects could contribute to the effectiveness of VNS in treatment-resistant depression.

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