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Int J Neuropsychopharmacol. 2014 Dec 28;18(6). pii: pyu102. doi: 10.1093/ijnp/pyu102.

The mood stabilizer lithium potentiates the antidepressant-like effects and ameliorates oxidative stress induced by acute ketamine in a mouse model of stress.

Author information

1
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD. chuang@mail.nih.gov chiuc@mail.nih.gov.
2
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.

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.

KEYWORDS:

BDNF; GSK-3; ketamine; lithium; mTOR

PMID:
25548109
PMCID:
PMC4438544
DOI:
10.1093/ijnp/pyu102
[Indexed for MEDLINE]
Free PMC Article

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