title: The mood stabilizer lithium potentiates the antidepressant-like effects and ameliorates oxidative stress induced by acute ketamine in a mouse model of stress.
abstract: BACKGROUND
  Evidence suggests that mammalian target of rapamycin activation mediates ketamine's rapid but transient antidepressant effects and that glycogen synthase kinase-3β inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine's antidepressant-like effects.
  
  
  METHODS
  Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated.
  
  
  RESULTS
  Subtherapeutic (600 mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5 mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50 mg/kg) injection were sustained by postketamine treatment with 1200 mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50 mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200 mg/L of lithium.
  
  
  CONCLUSIONS
  Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD. chuang@mail.nih.gov chiuc@mail.nih.gov.
authors.forename: Chi-Tso
authors.initials: CT
authors.lastname: Chiu
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Lisa
authors.initials: L
authors.lastname: Scheuing
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Guangping
authors.initials: G
authors.lastname: Liu
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Liao
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Linares
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Dora
authors.initials: D
authors.lastname: Lin
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD. chuang@mail.nih.gov chiuc@mail.nih.gov.
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
mesh_terms: D000339:Affect / Q000187:drug effects*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000633:toxicity; D018692:Antimanic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D019417:Hindlimb Suspension; D007649:Ketamine / Q000494:pharmacology* / Q000633:toxicity; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D018692:Antimanic Agents; D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D047428:Protein Kinase Inhibitors; D007649:Ketamine; C546843:mTOR protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride
keywords: BDNF; GSK-3; ketamine; lithium; mTOR