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.
Subject(s)
Adenosine Triphosphate/metabolism , Adrenocorticotropic Hormone/pharmacology , Deep Brain Stimulation/methods , Depression/physiopathology , Depression/therapy , Mitochondria/drug effects , Nucleus Accumbens/physiopathology , Affect/drug effects , Affect/physiology , Animals , Bipolar Disorder/physiopathology , Depression/psychology , Drug Resistance , Escape Reaction/drug effects , Escape Reaction/physiology , Imipramine/pharmacology , Male , Mitochondria/physiology , Motor Activity/drug effects , Motor Activity/physiology , Nucleus Accumbens/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiopathology , Premedication , Rats , Rats, WistarABSTRACT
The peripheral lymphocytes from 7 patients affected with ataxia telangiectasia (AT) were found to be about twice as sensitive to the induction of chromatid-type aberrations by X-rays administered during the G2 phase of the cell cycle as cells from normal controls. Peripheral lymphocytes from 6 AT heterozygotes were no more sensitive than the controls. Using labelling of peripheral lymphocytes with tritiated thymidine, followed by autoradiography, it was determined that cells from affected patients, heterozygotes and normal controls, whether irradiated or not, all had similar percent labeled mitoses (PLM) curves, so the increased induced aberration yields seen in the AT cells is not simply the consequence of a longer than normal G2 phase, nor of G2 delay induced by the radiation. Peripheral lymphocytes from two affected patients and two controls were irradiated in culture, labeled with tritiated thymidine and collected with colcemid over various intervals so that by scoring unlabeled cells in autoradiographs the time course of aberration yield over all of G2 could be determined. The curve for chromatid aberrations for the AT cells differ significantly from that for the controls in intercept, suggesting that in the AT cells the radiation induces more lesions capable of resulting in aberrations, but that their repair may be similar.
Subject(s)
Ataxia Telangiectasia/genetics , Chromatids/radiation effects , Chromosome Aberrations , Lymphocytes/radiation effects , Ataxia Telangiectasia/pathology , Cells, Cultured , Consanguinity , Female , Humans , Interphase , Lymphocytes/ultrastructure , Male , Pedigree , Radiation ToleranceABSTRACT
Contrary to an earlier report, peripheral lymphocytes from 4 AT patients were not found to exhibit higher yields of unequivocal chromosome type aberrations following irradiation in the G0 phase of the cell cycle, providing that only first post-irradiation metaphases were included in the samples (ensured by 5-bromodeoxyuridine (BrdU) incorporation and differential fluorescence or Giemsa staining). We were able, however, to confirm the earlier-reported increase in chromatid-type aberrations in the G0-irradiated cells. AT lymphocytes were found to experience more cell-cycle delay following G0 irradiation than normal cells. These observations appear consistent with the damaged base excision DNA-repair defect reported for AT cells.
