Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats

alterations in mitochondrial function relate to antidepressant-like effects

Y. Kim, S. McGee, J. K. Czeczor, A. J. Walker, R. P. Kale, A. Z. Kouzani, K. Walder, M. Berk, Susannah J Tye

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 μg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg(-1)) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 μA, 90 μS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation.

Original languageEnglish (US)
Pages (from-to)e842
JournalTranslational Psychiatry
Volume6
Issue number6
DOIs
StatePublished - Jun 21 2016
Externally publishedYes

Fingerprint

Deep Brain Stimulation
Nucleus Accumbens
Adrenocorticotropic Hormone
Antidepressive Agents
Imipramine
Prefrontal Cortex
Bipolar Disorder
Phenotype
Locomotion
Mood Disorders
Wistar Rats
Respiration
Animal Models
Adenosine Triphosphate
Therapeutics

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats : alterations in mitochondrial function relate to antidepressant-like effects. / Kim, Y.; McGee, S.; Czeczor, J. K.; Walker, A. J.; Kale, R. P.; Kouzani, A. Z.; Walder, K.; Berk, M.; Tye, Susannah J.

In: Translational Psychiatry, Vol. 6, No. 6, 21.06.2016, p. e842.

Research output: Contribution to journalArticle

Kim, Y. ; McGee, S. ; Czeczor, J. K. ; Walker, A. J. ; Kale, R. P. ; Kouzani, A. Z. ; Walder, K. ; Berk, M. ; Tye, Susannah J. / Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats : alterations in mitochondrial function relate to antidepressant-like effects. In: Translational Psychiatry. 2016 ; Vol. 6, No. 6. pp. e842.
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