Mitochondrial energy metabolism of rat hippocampus after treatment with the antidepressants desipramine and fluoxetine. (15th July 2017)

• Record Type: Journal Article
• Authors: Villa, Roberto Federico; Ferrari, Federica; Bagini, Laura; Gorini, Antonella; Brunello, Nicoletta; Tascedda, Fabio
• Is Part Of: Neuropharmacology. Volume 121(2017)
• Page Start: 30
• Page End: 38
• Publication Date: 2017-07-15
• Subjects: Desipramine -- Fluoxetine -- Mitochondria -- Functional proteomics -- Brain energy metabolism; 5-HT 5-hydroxytryptamine -- AD Antidepressant Drugs -- CBF Cerebral Blood Flow -- CCRS NADH-cytochrome c Reductase Rotenone-Sensitive -- CCRT NADH-cytochrome c Reductase as Total -- CMRglu Cerebral Metabolic Rate for Glucose -- CNS Central Nervous System -- COX Cytochrome Oxidase -- CS Citrate Synthase -- ETC Electron Transport Chain -- FM Non-synaptic Mitochondria -- FST Forced Swimming Test -- GlDH Glutamate Dehydrogenase -- HM Intra-synaptic Heavy Mitochondria -- LM Intra-synaptic Light Mitochondria -- MDH Malate Dehydrogenase -- NE Norepinephrine -- NGF Nerve Growth Factor -- OGI Oxygen-Glucose Index -- PET Positron Emission Tomography -- rCBF Regional Cerebral Blood Flow -- SA Specific Activity -- SD Sprague-Dawley -- SDH Succinate Dehydrogenase -- SSRI Selective Serotonin Reuptake Inhibitor -- TCA Tricyclic Antidepressant; Desipramine (PubChem CID: 2995) -- Fluoxetine Hydrochloride (PubChem CID: 62857); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.04.025
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Alterations in mitochondrial functions have been hypothesized to participate in the pathogenesis of depression, because brain bioenergetic abnormalities have been detected in depressed patients by neuroimaging in vivo studies. However, this hypothesis is not clearly demonstrated in experimental studies: some suggest that antidepressants are inhibitors of mitochondrial metabolism, while others observe the opposite. In this study, the effects of 21-day treatment with desipramine (15 mg/kg) and fluoxetine (10 mg/kg) were examined on the energy metabolism of rat hippocampus, evaluating the catalytic activity of regulatory enzymes of mitochondrial energy-yielding metabolic pathways. Because of the micro-heterogeneity of brain mitochondria, we have distinguished between (a) non-synaptic mitochondria (FM) of neuronal perikaryon (post-synaptic compartment) and (b) intra-synaptic light (LM) and heavy (HM) mitochondria (pre-synaptic compartment). Desipramine and fluoxetine changed the catalytic activity of specific enzymes in the different types of mitochondria: (a) in FM, both drugs enhanced cytochrome oxidase and glutamate dehydrogenase, (b) in LM, the overall bioenergetics was unaffected and (c) in HM only desipramine increased malate dehydrogenase and decreased the activities of Electron Transport Chain Complexes. These results integrate the pharmacodynamic features of desipramine and fluoxetine at subcellular level, overcoming the previous conflicting data about the effects of antidepressants on brain energy metabolism, mainly referred to whole brain homogenates or to bulk of cerebral mitochondria. With the differentiation in non-synaptic and intra-synaptic mitochondria, this study demonstrates that desipramine and fluoxetine lead to adjustments in the mitochondrial bioenergetics respect to the energy requirements of pre- and post-synaptic compartments. Highlights: Desipramine and fluoxetine effects on rat hippocampal energetics were assessed. Mitochondrial energy metabolism was studied by functional proteomics. Non-synaptic somatic mitochondria and intra-synaptic ones were purified. Energy metabolism increased in somatic mitochondria, decreased in intra-synaptic. The drugs modified enzyme activities coherently with their pharmacodynamics.