title: The antidepressant-like effect of vagus nerve stimulation is mediated through the locus coeruleus.
abstract: It has been shown that vagus nerve stimulation (VNS) has an antidepressant-like effect in the forced swim test. The mechanism of action underlying this effect is incompletely understood, but there is evidence suggesting that the locus coeruleus (LC) may play an important role. In this study, noradrenergic LC neurons were selectively lesioned to test their involvement in the antidepressant-like effect of VNS in the forced swim test. Forced swim test behavior was assessed in rats that were subjected to VNS or sham treatment. In half of the VNS-treated animals, the noradrenergic neurons from the LC were lesioned using the selective neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride], yielding three experimental arms: sham, VNS and DSP-4-VNS (n = 8 per group). Furthermore, the open field test was performed to evaluate locomotor activity. A dopamine-β-hydroxylase immunostaining was performed to confirm lesioning of noradrenergic LC neurons. VNS significantly reduced the percentage of immobility time in the forced swim test compared to sham treatment (median: 56%, interquartile range: 41% vs. median: 75%, interquartile range: 12%). This antidepressant-like effect of VNS could not be demonstrated in the DSP-4-VNS group (median: 79%, interquartile range: 33%). Locomotor activity in the open field test was not different between the three treatment arms. The absence of hippocampal dopamine-β-hydroxylase immunostaining in the DSP-4-treated rats confirmed the lesioning of noradrenergic neurons originating from the brainstem LC. The results of this study demonstrate that the noradrenergic neurons from the LC play an important role in the antidepressant-like effect of VNS.
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Annelies.Grimonprez@UGent.be.
authors.forename: Annelies
authors.initials: A
authors.lastname: Grimonprez
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Robrecht.Raedt@UGent.be.
authors.forename: Robrecht
authors.initials: R
authors.lastname: Raedt
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium; Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Jeanelle.Portelli@UGent.be.
authors.forename: Jeanelle
authors.initials: J
authors.lastname: Portelli
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Ine.Dauwe@Uzgent.be.
authors.forename: Ine
authors.initials: I
authors.lastname: Dauwe
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Larsemil.Larsen@UGent.be.
authors.forename: Lars Emil
authors.initials: LE
authors.lastname: Larsen
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Charlotte.Bouckaert@UGent.be.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bouckaert
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: JDelbeke@Gmail.com.
authors.forename: Jean
authors.initials: J
authors.lastname: Delbeke
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Evelien.Carrette@UGent.be.
authors.forename: Evelien
authors.initials: E
authors.lastname: Carrette
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Alfred.Meurs@UGent.be.
authors.forename: Alfred
authors.initials: A
authors.lastname: Meurs
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Veerle.DeHerdt@UGent.be.
authors.forename: Veerle
authors.initials: V
authors.lastname: De Herdt
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Paul.Boon@UGent.be.
authors.forename: Paul
authors.initials: P
authors.lastname: Boon
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent University, Department of Neurology, Institute for Neuroscience, Ghent, Belgium. Electronic address: Kristl.Vonck@UGent.be.
authors.forename: Kristl
authors.initials: K
authors.lastname: Vonck
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000627:therapeutic use*; D003863:Depression / Q000628:therapy*; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D018709:Statistics, Nonparametric; D013550:Swimming / Q000523:psychology; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D055536:Vagus Nerve Stimulation / Q000379:methods*
chemical_list: D001596:Benzylamines; D014179:Neurotransmitter Uptake Inhibitors; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; C012102:DSP 4
keywords: Depression; Forced swim test; Locus coeruleus; Noradrenaline; Vagus nerve stimulation