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

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

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J Psychiatry Neurosci 2010; 34(4): 272-280

Stella Manta, MSc; Jianming Dong, MD; Guy Debonnel, MD; Pierre Blier, MD, PhD

Manta, Blier — Institute of Mental Health Research, University of Ottawa, Ottawa, Ont.; Dong, Debonnel, Blier — Department of Psychiatry McGill University, Montréal Que.

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 CA3 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 α1-adrenoceptors on 5-HT neurons, probably through an increased release of endogenous NE. The tonic activation of postsynaptic 5-HT1A 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.

Conclusions: 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 α1-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.


Submitted Jun. 11, 2008; Revised Sep. 25, Dec. 23, 2008; Accepted Feb. 18, 2009

Acknowledgements: This work was supported by the Canadian Institutes of Health Research (University-Industry Program-Operating Grant UOP-71713) and by Cyberonics Inc., Houston, Texas. Dr. Blier received the Canadian Research Chair and is a paid consultant for Cyberonics. Cyberonics Inc. provided the leads, 102-pulse simulators and dummy simulators; they had no involvement in the research. We would like to thank Mrs. Lise Martin and Dr. Guillaume Lucas for great assistance.

Competing interests: None declared for Ms. Manta and Dr. Dong. Dr. Blier serves as president of Medical Multimedia Inc. and is a contract employee of Bristol-Myers Squibb, Forest Laboratories, Janssen Pharmaceuticals and Steelbeach Productions. He has received grant funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen Pharmaceuticals, Lundbeck, Mitsubishi Pharma, Organon Pharmaceuticals and Wyeth-Ayerst. He acts as a consultant to Biovail, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen Pharmaceuticals, Lundbeck, Novartis, Organon Pharmaceuticals, Pfizer, Sanofi-Aventis, Sepracor, Takeda and Wyeth- Ayerst and served on the speakers bureaus of Cyberonics, Eli Lilly, Forest Laboratories, Janssen Pharmaceuticals, Lundbeck, Organon Pharmaceuticals and Wyeth-Ayerst. Dr. Debonnel was a paid consultant for Cyberonics.

Contributors: Dr. Debonnel designed the study. Ms. Manta and Dr. Dong acquired the data, which Ms. Manta and Drs. Debonnel and Blier analyzed. Ms. Manta wrote the article, which Drs. Dong and Blier reviewed. Ms. Manta and Drs. Dong and Blier approved the final version for publication.

DOI: 10.1503/jpn.090175

Correspondence to: S. Manta, Institute of Mental Health Research (IMHR), University of Ottawa, 1145 Carling Ave., Suite 6412, Ottawa ON K1Z 7K4; stella.manta@rohcg.on.ca