Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects.
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.
School of Psychology, Faculty of Health, Deakin University, Melbourne, VIC, Australia.|Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
Y
Y
Kim
Centre for Molecular and Medical Research, School of Medicine, Faculty of Health, Deakin University, Melbourne, VIC, Australia.|Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
S
S
McGee
Centre for Molecular and Medical Research, School of Medicine, Faculty of Health, Deakin University, Melbourne, VIC, Australia.
J K
JK
Czeczor
School of Psychology, Faculty of Health, Deakin University, Melbourne, VIC, Australia.|Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
A J
AJ
Walker
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.|School of Engineering, Faculty of Science Engineering and Built Environment, Deakin University, Geelong, VIC, Australia.
R P
RP
Kale
School of Engineering, Faculty of Science Engineering and Built Environment, Deakin University, Geelong, VIC, Australia.
A Z
AZ
Kouzani
Centre for Molecular and Medical Research, School of Medicine, Faculty of Health, Deakin University, Melbourne, VIC, Australia.
K
K
Walder
Deakin University IMPACT Strategic Research Centre, School of Medicine, Faculty of Health, Geelong, VIC, Australia.
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M
Berk
School of Psychology, Faculty of Health, Deakin University, Melbourne, VIC, Australia.|Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.|Department of Psychiatry, University of Minnesota, Rochester, MN, USA.
S J
SJ
Tye
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000339:Affect / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001714:Bipolar Disorder / Q000503:physiopathology; D046690:Deep Brain Stimulation / Q000379:methods*; D003863:Depression / Q000503:physiopathology* / Q000523:psychology / Q000628:therapy*; D004351:Drug Resistance; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011292:Premedication; D051381:Rats; D017208:Rats, Wistar
D000255:Adenosine Triphosphate; D000324:Adrenocorticotropic Hormone; D007099:Imipramine