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Mol Neurobiol DOI 10.1007/s12035-015-9580-9

Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway Francis L. Pazini 1 & Mauricio P. Cunha 1 & Julia M. Rosa 1 & André R. S. Colla 1 & Vicente Lieberknecht 1 & Ágatha Oliveira 1 & Ana Lúcia S. Rodrigues 1

Received: 24 September 2015 / Accepted: 29 November 2015 # Springer Science+Business Media New York 2015

Abstract Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 μg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced

* Ana Lúcia S. Rodrigues [email protected] 1

Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, Santa Catarina 88040-900, Brazil

depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant. Keywords Akt . Corticosterone . Creatine . Ketamine . mTOR . Tail suspension test

Abbreviations Akt/PKB Protein kinase B AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid ANOVA Analysis of variance BDNF Brain-derived neurotrophic factor CORT Corticosterone DMSO Dimethyl sulfoxide ERK Extracellular signal-regulated kinase FST Forced swimming test GluA1 AMPA receptor subunit HPA Hypothalamic pituitary adrenal i.c.v. Intracerebroventricular i.p. Intraperitoneal MEK Mitogen-activated protein kinase mTOR Mammalian target of rapamycin NMDA N-methyl D-aspartate OD Optical density OFT Open field test p.o. per os p70S6K p70S6 kinase PI3K Phosphatidylinositol-3-kinase PSD95 Postsynaptic density-95 protein

Mol Neurobiol

TrkB TST

Tropomyosin-related kinase receptor B Tail suspension test.

Introduction Major depression is a high prevalent psychiatric disorder that affects approximately 17 % of the population over the life course, causing serious personal and socioeconomic consequences [1]. Approximately one in six men and one in four women will experience a depressive episode throughout life [2]. It is a disorder characterized by a broad range of symptoms, including depressed mood, impaired cognitive functions, and recurrent thoughts of death or suicide. As opposed to normal experiences of sadness, major depression is a chronic disease which may significantly interfere in the individual’s life quality [3]. Clinical observations have demonstrated that exposure to stress is associated with depressive disorders, which may be accompanied by increased or even decreased serum cortisol levels [4]. Based on this background, a preclinical model of depression based on the repeated administration of corticosterone (CORT) in rodents has been used to investigate novel antidepressant agents, since it induces behavioral and neurological alterations that mimic some core symptoms observed in depressive patients [5]. Chronic exposure to CORT is able to induce a depressive-like behavior characterized by reduced sucrose consumption [6], and increased immobility time in the forced swimming test (FST) [7] and tail suspension test (TST) [8]. Furthermore, CORT treatment produces adult neurogenesis deficit in the hippocampus of rodents [9, 10] by reducing the levels of hippocampal and cerebrocortical brain-derived neurotrophic factor (BDNF) [11–14], a neurotrophin that plays pivotal functions in the central nervous system such as cell differentiation, neuronal survival, migration, and synaptic plasticity [15]. Additionally, several studies have shown that chronic administration of antidepressants, such as amitriptyline and fluoxetine, prevents the depressive-like behavior induced by CORT treatment in rodents [16, 17]. A major limitation of available monoaminergic-based antidepressant drugs, such as fluoxetine, is their long lag period for affording therapeutic effects, which often approaches 4– 6 weeks. Therefore, a special interest has been given to the glutamatergic system as potential therapeutic target for the management of depression [18, 19]. Of note, clinical studies have shown that the N-methyl D-aspartate (NMDA) receptor antagonist ketamine exerts rapid antidepressant effects [20, 21]. Notably, a single administration of ketamine has been reported to be able to reverse the behavioral deficits in models of depression that are only responsive to chronic administration of conventional antidepressants, such as the chronic unpredictable stress [22].

Although the mechanisms underlying the rapid and robust effects of ketamine are not completely understood, preclinical studies have shown that its effects are mediated by a fast, but transient activation of the mammalian target of rapamycin (mTOR) pathway in rat prefrontal cortex and hippocampus [23, 24]. Activation of mTOR signaling stimulates messenger RNA (mRNA) translation and protein synthesis by activating of p70S6 kinase (p70S6K), causing rapid and sustained elevation of synapse-associated proteins, including postsynaptic density-95 protein (PSD95), which is responsible for several functions, including scaffold and organization of receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [25]. Phosphatidylinositol-3-kinase (PI3K) catalyzes the phosphorylation of phosphatidylinositol lipids at the 3 position of the inositol ring in response to cell stimulation by growth factors, hormones, and cytokines [26]. Several studies have implicated PI3K in synaptic plasticity, learning and memory, and major depression [27, 28]. Lipid products formed by PI3K activation, act as second messengers by recruiting proteins, such as protein kinase B (PKB/Akt), resulting in the activation of its downstream kinases, possibly by a mechanism dependent on the synthesis and release of BDNF, with the consequent increase in mTOR phosphorylation [25]. Although results with ketamine are encouraging, most patients experience transient dissociation, psychotomimetic side effects and hemodynamic changes (e.g., increases in blood pressure and heart rate), besides dysphoria, euphoria, and/or anxiety during infusion, factors that limit its clinical use [29]. The investigation and discovery of compounds that can produce ketamine-like effects with a safer side effect profile and decreased abuse liability may represent an important advance in the field of depression. Our group and others have demonstrated that creatine, an ergogenic guanidine-like compound that possesses neuroprotective effects [30–32], exhibits an antidepressant-like effect in TST and FST, two predictive tests of antidepressant properties [33–36]. Moreover, clinical studies have shown that creatine is a promising therapeutic approach for depression, since some data have indicated that it exhibits rapid and efficacious antidepressant responses when administered in combination with selective serotonin reuptake inhibitors [37, 38]. Taking into account that a previous study published by our group demonstrated that an acute treatment of mice with creatine increased hippocampal Akt and P70S6K p ho sph or yla tio n a nd PSD9 5 lev els , a nd th at its antidepressant-like effect in the TST is dependent on PI3K/Akt/mTOR activation [39], we hypothesized that this compound may exhibit ketamine-like biochemical and behavioral effects. Therefore, the aim of this study was to examine the ability of a single dose of creatine to reverse behavioral and neurochemical effects in a model of depression induced by chronic administration of CORT, and whether the behavioral response

Mol Neurobiol

to creatine, similarly to ketamine in this model, is dependent on the modulation of mTOR and its up and downstream signaling targets, PI3K, p70S6K, PSD95, and BDNF, in the hippocampus, a brain structure closely implicated in depressive disorders [40].

Materials and Methods

injection was given over 30 s, and the needle remained in place for another 30 s in order to avoid the reflux of the substances injected. The injection site was 1 mm to the left from the midpoint on a line drawn through to the anterior base of the ears. Then, i.c.v. injections were performed by an experienced investigator, and after dissection of the brain of the animal, the success of the injection was examined, macroscopically, discarding results from mice presenting misplacement of the injection site or any sign of cerebral hemorrhage (