title: Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release.
abstract: BACKGROUND
  Medial forebrain bundle (MFB) deep brain stimulation (DBS) is currently being investigated in patients with treatment-resistant depression. Striking features of this therapy are the large number of patients who respond to treatment and the rapid nature of the antidepressant response.
  
  
  OBJECTIVE
  To study antidepressant-like behavioral responses, changes in regional brain activity, and monoamine release in rats receiving MFB DBS.
  
  
  METHODS
  Antidepressant-like effects of MFB stimulation at 100 μA, 90 μs and either 130 Hz or 20 Hz were characterized in the forced swim test (FST). Changes in the expression of the immediate early gene (IEG) zif268 were measured with in situ hybridization and used as an index of regional brain activity. Microdialysis was used to measure DBS-induced dopamine and serotonin release in the nucleus accumbens.
  
  
  RESULTS
  Stimulation at parameters that approximated those used in clinical practice, but not at lower frequencies, induced a significant antidepressant-like response in the FST. In animals receiving MFB DBS at high frequency, increases in zif268 expression were observed in the piriform cortex, prelimbic cortex, nucleus accumbens shell, anterior regions of the caudate/putamen and the ventral tegmental area. These structures are involved in the neurocircuitry of reward and are also connected to other brain areas via the MFB. At settings used during behavioral tests, stimulation did not induce either dopamine or serotonin release in the nucleus accumbens.
  
  
  CONCLUSIONS
  These results suggest that MFB DBS induces an antidepressant-like effect in rats and recruits structures involved in the neurocircuitry of reward without affecting dopamine release in the nucleus accumbens.
authors.affiliation: Behavioural Neurobiology Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Bregman
authors.affiliation: Behavioural Neurobiology Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8.
authors.forename: Roman
authors.initials: R
authors.lastname: Reznikov
authors.affiliation: Behavioural Neurobiology Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8.
authors.forename: Mustansir
authors.initials: M
authors.lastname: Diwan
authors.affiliation: Behavioural Neurobiology Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8.
authors.forename: Roger
authors.initials: R
authors.lastname: Raymond
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT, USA; Scientific Computing & Imaging Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Butson
authors.affiliation: Behavioural Neurobiology Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8.
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
authors.affiliation: Behavioural Neurobiology Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8; Division of Neurosurgery, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8. Electronic address: Clement.Hamani@camh.ca.
authors.forename: Clement
authors.initials: C
authors.lastname: Hamani
mesh_terms: D000818:Animals; D000928:Antidepressive Agents; D001921:Brain / Q000378:metabolism; D046690:Deep Brain Stimulation; D004298:Dopamine / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis; D046353:Immobility Response, Tonic / Q000502:physiology*; D008297:Male; D008474:Medial Forebrain Bundle / Q000502:physiology*; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D012201:Reward; D012701:Serotonin / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D012701:Serotonin; D004298:Dopamine
keywords: Deep brain stimulation; Depression; Dopamine; Medial forebrain bundle; Nucleus accumbens; Serotonin; Stimulation