title: Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle.
abstract: Among several potential neuroanatomical targets pursued for deep brain stimulation (DBS) for treating those with treatment-resistant depression (TRD), the superolateral-branch of the medial forebrain bundle (MFB) is emerging as a privileged location. We investigated the antidepressant-like phenotypic and chemical changes associated with reward-processing dopaminergic systems in rat brains after MFB-DBS.
  
  
  
  Male Wistar rats were divided into three groups: sham-operated, DBS-Off, and DBS-On. For DBS, a concentric bipolar electrode was stereotactically implanted into the right MFB. Exploratory activity and depression-like behavior were evaluated using the open-field and forced-swimming test (FST), respectively. MFB-DBS effects on the dopaminergic system were evaluated using immunoblotting for tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine receptors (D1-D5), and high-performance liquid chromatography for quantifying dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in brain homogenates of prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc).
  
  
  
  Animals receiving MFB-DBS showed a significant increase in swimming time without alterations in locomotor activity, relative to the DBS-Off (p<0.039) and sham-operated groups (p<0.014), indicating an antidepressant-like response. MFB-DBS led to a striking increase in protein levels of dopamine D2 receptors and DAT in the PFC and hippocampus, respectively. However, we did not observe appreciable differences in the expression of other dopamine receptors, TH, or in the concentrations of dopamine, DOPAC, and HVA in PFC, hippocampus, amygdala, and NAc.
  
  
  
  This study was not performed on an animal model of TRD.
  
  
  
  MFB-DBS rescues the depression-like phenotypes and selectively activates expression of dopamine receptors in brain regions distant from the target area of stimulation.
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX, USA.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Dandekar
authors.affiliation: The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Department of Neurosurgery, Houston, TX, USA.
authors.forename: Dustin
authors.initials: D
authors.lastname: Luse
authors.affiliation: The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Department of Neurosurgery, Houston, TX, USA.
authors.forename: Carson
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Department of Neurosurgery, Houston, TX, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cotton
authors.affiliation: The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Department of Neurosurgery, Houston, TX, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Peery
authors.affiliation: The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Department of Neurosurgery, Houston, TX, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hussey
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX, USA.
authors.forename: Vijayasree V
authors.initials: VV
authors.lastname: Giridharan
authors.affiliation: Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX, USA.
authors.forename: Jair C
authors.initials: JC
authors.lastname: Soares
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX, USA; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX, USA; Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil.
authors.forename: Joao
authors.initials: J
authors.lastname: Quevedo
authors.affiliation: The University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Department of Neurosurgery, Houston, TX, USA. Electronic address: Albert.J.Fenoy@uth.tmc.edu.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fenoy
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D046690:Deep Brain Stimulation / Q000379:methods; D061218:Depressive Disorder, Treatment-Resistant / Q000378:metabolism / Q000628:therapy*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D008297:Male; D008474:Medial Forebrain Bundle / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: Deep brain stimulation; Depression; Dopamine; FST; MFB