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 (600mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5mg/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 (50mg/kg) injection were sustained by postketamine treatment with 1200mg/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 (50mg/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 1200mg/L of lithium.Conclusions:Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.

Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease

“…Compatibly, Petit-Paitel et al have depicted that either pharmacological or genetically inhibition of GSK-3␤ (LiCl and kenpaullone, and RNA interference) could abrogate MPP+ mediated mitochondrial membrane potential changes and subsequent caspase-9 and -3 activations [101]. As mentioned, GSK-3␤ is involved in oxidative damages seen in PD, therefore fighting against oxidative stress by GSK-3␤ inhibitors is another potential treatment choice for PD, in accordance to this theory evidences are available showing that different GSK-3␤ inhibitors such as lithium and BIP-135 could abrogate oxidative damages in neuronal models of oxidative stress [160,161]. Preventing ER stress induction is another possible way that might contribute to the efficiency of GSK-3 inhibitors against PD; persistently it has been shown that pretreatment with GSK-3 inhibitors such as lithium significantly reduces CHOP expression [162].…”

Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition

“…Ketamine can induce rapid antidepressant effects in depressed patients with mood disorders (Newport et al, 2015; Niciu et al, 2014; Scheuing et al, 2015) and the antidepressant mechanism of action of ketamine is linked to GSK3 inhibition (Beurel et al, 2011; Chiu et al, 2014; Ghasemi et al, 2010; Liu et al, 2013; Yang et al, 2013; Zhou et al, 2014). Here we found that up-regulation of IGF2 expression in mouse hippocampus appears to contribute to the GSK3 inhibition-dependent antidepressant effect of ketamine in mice.…”

“…Ketamine treatment fails to induce an antidepressant effect in GSK3 knockin mice, demonstrating the necessity for ketamine-induced inhibitory serine-phosphorylation of GSK3 for this effect (Beurel et al, 2011). Further studies showed that administration of GSK3 inhibitors enhanced the antidepressant effects of ketamine (Chiu et al, 2014; Ghasemi et al, 2010; Liu et al, 2013). Thus, ketamine-induced inhibition of GSK3 is linked to its antidepressant action, but it remains unknown how this contributes to the antidepressant effects of ketamine (Zunszain et al, 2013).…”

Anti-stress effects of a GSK-3β inhibitor, AR-A014418, in immobilization stress of variable duration in mice

“…The administration of flupirtine (a centrally acting, non-opioid analgesic) attenuates the stress-induced deleterious effects by decreasing GSK-3β activity, suggesting the role of activation of GSK-3β signaling pathways during stress induction [14]. The administration of lithium, a GSK-3β inhibitor, potentiates the antidepressant-like effects of ketamine in a mouse model of stress [15]. However, there has also been a study showing that the administration of a GSK-3β inhibitor does not affect the immobility time in chronic unpredictable stress-subjected animals [16].…”