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

J Psychiatry Neurosci. 2009 Jul;34(4):272-80.


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 alpha(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 alpha(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adrenergic Agents / pharmacology
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Benzylamines / pharmacology
  • Hippocampus / physiology
  • Locus Coeruleus / metabolism
  • Locus Coeruleus / physiology*
  • Neurons / metabolism
  • Neurons / physiology
  • Norepinephrine / metabolism
  • Norepinephrine / physiology*
  • Piperazines / pharmacology
  • Prazosin / pharmacology
  • Pyramidal Cells / physiology
  • Pyridines / pharmacology
  • Raphe Nuclei / metabolism
  • Raphe Nuclei / pathology
  • Raphe Nuclei / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism
  • Serotonin / physiology*
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists / pharmacology
  • Vagus Nerve Stimulation / methods*


  • Adrenergic Agents
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Benzylamines
  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists
  • Serotonin
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • DSP 4
  • Norepinephrine
  • Prazosin