Life Sciences 101 (2014) 10–14
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Life Sciences journal homepage: www.elsevier.com/locate/lifescie
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The role of mTOR in depression and antidepressant responses Helena M. Abelaira a, Gislaine Z. Réus a,b,⁎, Morgana V. Neotti a, João Quevedo a,b a b
Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA
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Article history: Received 10 October 2013 Accepted 14 February 2014 Available online 25 February 2014 Keywords: mTOR Antidepressants Ketamine Depression
a b s t r a c t The aim of this study was to characterize the mTOR signaling cascade in depression and the actions that antidepressant drugs have on this pathway. Herein, a literature review was performed by verification and comparison of textbooks and journal articles that describe the characterization of the mTOR signaling cascade and its relationship to depression and antidepressant drugs, especially ketamine. Postmortem studies have shown robust deficits in the mammalian target of rapamycin (mTOR) signaling in the prefrontal cortex of subjects diagnosed with major depressive disorder. However, besides the mTOR signaling pathway having an antidepressant response to various drugs, this seems to be more associated with antidepressant N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine. The characterization of the mTOR signaling pathway in depression and its action in response to antidepressants show great potential for the identification of new therapeutic targets for the development of antidepressant drugs. © 2014 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major depression . . . . . . . . . . . . . . . . . . . . . . . . . . mTOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The mTOR signaling cascade and its relationship with antidepressants Conclusions and future remarks . . . . . . . . . . . . . . . . . . .
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Conflicts of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Introduction Depression is a serious disorder that has enormous consequences for the quality of life, and is one of the most prevalent forms of mental illness (Larsen et al., 2010). It is a clinically and biologically heterogeneous disorder, with 10%–30% of women and 7%–15% of men likely to suffer from depression in their lifetime (Briley, 2000). Moreover, patients suffering from severe depression have high rates of morbidity and mortality, with profound economic and social consequences (Nemeroff and Owens, 2002). Serotonin and/or norepinephrine reuptake inhibitors are widely used to alleviate the symptoms
⁎ Corresponding author at: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil. Fax: +55 48 3431 2736. E-mail address: [email protected] (G.Z. Réus).
http://dx.doi.org/10.1016/j.lfs.2014.02.014 0024-3205/© 2014 Elsevier Inc. All rights reserved.
of depression in clinical practice. Unfortunately, the delayed onset time and the low remission rate of these conventional antidepressants are still major challenges (Machado-Vieira et al., 2009) Therefore, there is an urgent need to look for a fast-acting and effective antidepressant in the near future. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates the initiation of protein translation, and is expressed in dendritic development that controls new protein synthesis (Duman et al., 2012). Li et al (2010) have reported that the activation of mTOR in the prefrontal cortex underlies the antidepressant effects of ketamine in rats. Some case studies have also reported that mTOR is activated in depressed patients' peripheral blood after acute ketamine administration (Denk et al., 2011; Yang et al., 2013). In this case, the purpose of the present review is to offer an overview of the current knowledge about depression and the mTOR signaling pathway and the relationship that the mTOR signaling cascade has with depression and with antidepressants drugs.
H.M. Abelaira et al. / Life Sciences 101 (2014) 10–14
Major depression The mental disorder known as major depression is the most common mood disorder, affecting 5% of the population every year (Kessler and Wang, 2008; Lopez and Mathers, 2006). The main symptoms include depressed mood and diminished interest or pleasure in all activities. Other symptoms may also occur, including loss (or increase) in appetite, insomnia (or excessive sleep), fatigue, feelings of worthlessness and guilt, difficulty concentrating, and recurrent thoughts about death, among others (Krishnan and Nestler, 2008). Major depressive disorder (MDD) is currently treated with agents that increase neurotransmission monoaminergics, and the main monoamines that are related to depression are serotonin and/or noradrenaline. It is generally agreed that increased monoamine transmission initiates cellular adaptations that ultimately lead to therapeutic action (Warner-Schmidt et al., 2010). Identification and ultimately more direct targeting of these downstream mediators could lead to novel therapeutics that are both faster acting and produce fewer off-target effects. Treatment of depression is generally safe and effective but is far from ideal because the latency time for clinical benefit is relatively long (this period lasts between 3 and 5 weeks) and there are still major problems concerning side effects such as loss of libido and weight gain, among others. Although therapy for depression with drugs, psychotherapy and electroconvulsive therapy are effective, a significant number of patients do not respond well to these treatments (Anderson, 1996; Berton and Nestler, 2006). These findings suggest that adaptive changes in cellular signaling cascades (e.g., the brain-derived neurotrophic factor (BDNF)– TrkB receptor signaling pathway) may be responsible for the therapeutic effects of these drugs (Hashimoto, 2009; Lanni et al., 2009). Accumulating evidence suggests that psychotropic agents such as antidepressants realize their neurotrophic/neuroprotective effects by activating the mitogen-activated protein kinase (MAPK/ERK), phosphatidylinositol 3-kinase (PI3K), and glycogen synthase kinase 3 Wnt/GSK-3 signaling pathways. These agents also upregulate the expression of trophic/protective molecules such as BDNF, nerve growth factor (NGF), B-cell lymphoma 2 (Bcl-2), thymoma viral protooncogene (AKT) and BCL2-associated athanogene (BAG-1) and inactivate proapoptotic molecules such as GSK-3 (Hunsberger et al., 2009). However, in addition to this, Krishnan and Nestler (2008) and McKernan et al. (2009) demonstrated that BDNF and NGF activate
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signaling pathways involved in the upregulation of the expression of anti-apoptotic protein Bcl-2, B-cell lymphoma-extra large (Bcl-xl) and Bcl-2-associated x protein (Bax). Thus, it has been proposed that antidepressants elicit their effect by inducing the expression of neurotrophins while targeting apoptotic proteins at the same time, which results in blocking or even reversing apoptosis-induced structural alterations in limbic structures (McKernan et al., 2009; Banasr et al., 2011). mTOR The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, also known as a mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1), which modulates cell proliferation, mortality, survival and protein synthesis (Hay and Sonenberg, 2006). This serine/threonine kinase also belongs to the phosphatidylinositol 3-kinase-related kinase protein (PIKK) family. The mTOR pathway is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers (Beevers et al., 2006; Cornu et al., 2013; Zoncu et al., 2011). Human mTOR gene encodes a protein of 2549 amino acids with 42% and 45% sequence identity to yeast TOR1 and TOR2, respectively (Wullschleger et al., 2006). mTOR Complex 1 (mTORC1) is characterized by the classic features of mTOR by functioning as a nutrient/energy/ redox sensor and controlling protein synthesis (Kim et al., 2002). The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress (Kim et al., 2003) (Fig. 1). mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers; paxillin; ras homolog gene family, member A (RhoA); ras-related C3 botulinum toxin substrate 1 (Rac1); cell division cycle 42 (Cdc42); and protein kinase C α (PKCα) (Sarbassov et al., 2004). mTORC2 also appears to possess the activity of a previously elusive protein known as pyruvate dehydrogenase kinase isoform 2 (PDK2) and phosphorylates the serine/threonine protein kinase Akt/PKB at serine residue S473 (Sarbassov et al., 2005; Stephens et al., 1998) (Fig. 2). Both mTOR complexes are large, with mTORC1 having six and mTORC2 seven known protein components. They share the catalytic mTOR subunit and also mammalian lethal with sec-13 protein 8 (mLST8, also known as GbL) (Jacinto et al., 2004; Kim et al., 2003), DEP domain containing mTOR-interacting protein (DEPTOR) (Peterson
Fig. 1. mTORC1 complex. The mTORC1 complex responds to amino acids, oxidative stress, insulin, growth factors, serum and phosphatidic acid. mTORC1 promotes protein synthesis.
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Fig. 2. mTORC2 complex. The mTORC2 complex responds to growth factors and promotes the regulation of Akt/PKB, pyruvate dehydrogenase kinase isoform 2 (PDK2) and cytoskeleton through its stimulation of F-actin stress fibers; paxillin; ras homolog gene family, member A (RhoA); ras-related C3 botulinum toxin substrate 1 (Rac1); cell division cycle 42 (Cdc42); and protein kinase C α (PKCα).
et al., 2009), and the TELO2 interacting protein 1/telomere maintenance 2 (Tti1/Tel2) complex (Kaizuka et al., 2010). However, the mechanisms that activate or induce the mTOR signaling cascade are still unclear. The requirement for glutamate-AMPA (adhesion modulation protein A) receptor activation is consistent with the hypothesis that there is a subset of N-methyl-D-aspartate (NMDA) receptors, possibly on GABAergic interneurons, that when activated leads to disinhibition of glutamate signaling (Farber et al., 1998; Li et al., 2010). Thus, further characterization of these actions of NMDA receptor blockade and signaling pathways that stimulate mTOR signaling and mediate the rapid induction of synapses in the hippocampus, amygdala, prefrontal cortex and striatum will provide novel therapeutic targets for antidepressant drug development (Li et al., 2010). The mTOR signaling cascade and its relationship with antidepressants Many studies have highlighted the role of the NMDA receptor in depression. Accordingly, deficits in prominent postsynaptic proteins, including NMDA receptor subunits (NR2A and NR2B) and metabotropic glutamate receptor subtype 5 (mGlur5), were previously demonstrated in the prefrontal cortex from depressed subjects (Chandran et al., 2013; Deschwanden et al., 2011; Feyissa et al., 2009). Based on these studies, it is tempting to hypothesize that an activation of mTOR function followed by enhanced mTOR-dependent protein synthesis may underlie the action of antidepressants, such as ketamine (Chandran et al., 2013; Dwyer et al., 2012; Li et al., 2010, 2011). Ketamine is used clinically as a dissociative anesthetic (Martin and Lodge, 1985) and not only acts as an antagonist of the NMDA receptor, but it also interacts with channels and with voltage-sensitive Ca2+ opioid, monoamine and muscarinic receptors (Hirota and Lambert, 1996). Ketamine stimulation of mTOR signaling and antidepressant behavioral actions is dependent on glutamate-AMPA receptor activation (Duman et al., 2012). Drug targets that enhance glutamate transmission or activate AMPA receptors could also produce rapid and efficacious antidepressant action.
Recently, clinical observations have shown that sub-anesthetic doses of ketamine produce therapeutic effects in patients with depression (Berman et al., 2000; Correll and Futter, 2006). Postmortem studies showed robust deficits in mTOR signaling in the prefrontal cortex of subjects diagnosed with MDD (Chandran et al., 2013). Recent studies with animals indicate that the fast antidepressant response to NMDA receptor antagonists, such as ketamine, is mediated by rapid activation of the mTOR pathway leading to an increase in synaptic signaling proteins and an increased number and function of new spine synapses in the prefrontal cortex of rats (Li et al., 2010). Furthermore, Chandran et al. (2013) demonstrated that an eight-week chronic unpredictable stress (CUS) exposure produces deficits in the mTOR signaling pathway components in the amygdala. Moreover, it has been demonstrated that a single dose of ketamine rapidly reversed the chronic stress-induced behavior and synaptic deficits in an mTOR-dependent manner (Li et al., 2011). Hoeffer and Klann (2010) showed that ketamine produced a similar rapid and transient increase in the phosphorylated and activated forms of extracellular signal-regulated kinase (ERK, including ERK1 and ERK2) and protein kinase B (PKB/AKT) growth factor signaling pathways that have been linked to the activation of mTOR signaling. Still, Yu et al. (2013) showed that inhibition of mTOR by rapamycin reversed the antidepressant effects of ketamine in depressive patients. Nevertheless, unlike ketamine, other antidepressant treatment such as imipramine inhibited PI3K/Akt/mTOR signaling (Jeon et al., 2011). However, Warren et al. (2011) demonstrated that administration of fluoxetine in combination with methylphenidate induced mTOR activity in rats, and Lin et al. (2010) showed that sertraline exerts antiproliferative activity by targeting the mTOR signaling pathway in rat embryonic fibroblasts. Furthermore, besides the classic antidepressants, there are other drugs that have antidepressant effects and present an effect on mTOR signaling. Concomitant with this, Lauterbach (2012) demonstrated that dextromethorphan (DXM) directly influences mTOR signaling. DXM is an antitussive drug, but recently, the hypothesis was offered that DXM may have a potential as a rapidly acting antidepressant
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based on pharmacodynamic similarities to ketamine (Lauterbach, 2011). Yang et al. (2012) showed that pretreatment with tramadol enhanced the ketamine-induced antidepressant effects and upregulated the expression of mTOR in rat hippocampus and prefrontal cortex. Tramadol is a widely used analgesic agent, which exerts therapeutic effects via activation of opioid receptors and elevation of the plasma levels of serotonin and norepinephrine (Barber, 2011). As already mentioned, conventional antidepressants produce their effectiveness by increasing the level of monoamines, which share identical mechanisms of action to tramadol (Yang et al., 2012). However, unlike ketamine, these drugs have different effects on mTOR activity in the brain. These effects can be explained by the different mechanisms of action of these drugs, especially in the monoaminergic system. mTOR signaling activation by ketamine has been reported to be completely blocked by 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), an AMPA receptor antagonist. The mechanisms by which mGlu2/3 receptor antagonists activate mTOR signaling may be partly different from ketamine. Furthermore, stimulation of the AMPA receptor may be involved in the activation of mTOR signaling using mGLU2/3 receptor antagonists. This hypothesis is supported by Antion et al. (2008), who reported that the mGlu (mGlu1/5) receptor regulates mTOR signaling and that the mGlu1/5 receptor agonist, 3,5-dihydroxyphenylglycine, increased translation of synaptic related proteins, such as PSD-95, GluR1 and GluR2 in the cortex (Muddashetty et al., 2007). Conclusions and future remarks A number of studies have shown an association between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD. However, besides the mTOR signaling pathway having an antidepressant response to various drugs, this seems to be more associated with antidepressant NMDA receptor antagonists, such as ketamine. Thus, more studies are needed to characterize the mTOR signaling pathway in depression and their participation in antidepressant mechanisms. Further research will provide a great potential for the identification of new therapeutic targets for the development of antidepressant drugs. Conflicts of interest statement The authors have declared that no conflicts of interest exist relevant to the current manuscript.
Acknowledgments Laboratory of Neurosciences (Brazil) is a center within the National Institute for Translational Medicine (INCT-TM) and is also a member of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (JQ and GZR), FAPESC (JQ), Instituto Cérebro e Mente and UNESC (JQ). JQ is CNPq Research Fellows. GZR and HMA have CAPES studentships. References Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a attenuates the effects of antidepressants on the forced swim test in rats. Brain Res 1996;709:215–20. Antion MD, Hou L, Wong H, Hoeffer CA, Klann E. mGluR-dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of elongation factor 1A but remains expressed in S6K-deficient mice. Mol Cell Biol 2008;28:2996–3007. Banasr M, Dwyer JM, Duman RS. Cell atrophy and loss in depression: reversal by antidepressant treatment. Curr Opin Cell Biol 2011;23:730–7. Barber J. Examining the use of tramadol hydrochloride as an antidepressant. Exp Clin Psychopharmacol 2011;19:123–30. Beevers C, Li F, Liu L, Huang S. Curcumin inhibits the mammalian target of rapamycinmediated signaling pathways in cancer cells. Int J Cancer 2006;119:757–64. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47(4):351–4. Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006;7:137–51. Briley M, Moret C. Present and future anxiolytics. IDrugs 2000;3:695–9.
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Chandran A, Iyo AH, Jernigan CS, Legutko B, Austin MC, Karolewicz B. Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog Neuropsychopharmacol Biol Psychiatry 2013;40:240–5. Cornu M, Albert V, Hall MN. mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev 2013;23(1):53–62. Correll GE, Futter GE. Two case studies of patients with major depressive disorder given low-dose (subanesthetic) ketamine infusions. Pain Med 2006;7(1):92–5. Denk MC, Rewerts C, Holsboer F, Erhardt-Lehmann A, Turck CW. Monitoring ketamine treatment response in a depressed patient via peripheral mammalian target of rapamycin activation. Am J Psychiatry 2011;68(1):751–2. Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A, et al. Reduced metabotropic glutamate receptor 5 density in major depression determined by ABP688 PET and postmortem study. Am J Psychiatry 2011;168:727–34. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012;62:35–41. Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the antidepressant effects of mGluR2/3 blockade. Int J Neuropsychopharmacol 2012;15:429–34. Farber NB, Newcomer JW, Olney JW. The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer's disease. Prog Brain Res 1998;116:421–37. Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:70–5. Hashimoto K. Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 2009;6:105–23. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2006;18:1926–45. Hirota K, Lambert DJ. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth 1996;77:441–4. Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 2010;33:67–75. Hunsberger J, Austin DR, Henter ID, Chen G. The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues Clin Neurosci 2009;11:333–48. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6: 1122–8. Jeon SH, Kim Y, Kim YS, Lim Y, Lee YH, Shin SY. The tricyclic antidepressant imipramine induces autophagic cell death in U87MG gliom cells. Biochem Biophys Res Commun 2011;23:311–7. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, et al. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 2010;28:20109–16. Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu Rev Public Health 2008;29:115–29. Kim D, Sarbassov D, Ali S, King J, Latek R, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002:163–75. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003;11:895–904. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455: 894–902. Lanni C, Govoni S, Lucchelli A, Boselli C. Depression and antidepressants: molecular and cellular aspects. Cell Mol Life Sci 2009;66:2985–3008. Larsen MH, Mikkelsen JD, Hay-Schmidt A, Sandi C. Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment. J Psychiatr Res 2010;44:808–16. Lauterbach EC. Dextromethorphan as a potential rapid-acting antidepressant. Med Hypotheses 2011;76:717–9. Lauterbach EC. An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan. Med Hypotheses 2012;78:693–702. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;20:959–64. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011;69:754–61. Lin CJ, Robert F, Sukarieh R, Michnick S, Pelletier J. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Res 2010;15:3199–208. Lopez AD, Mathers CD. Measuring the global burden of disease and epidemiological transitions: 2002–2030. Ann Trop Med Parasitol 2006;100:481–99. Machado-Vieira R, Salvadore G, Diazgranados N, Zarate Jr CA. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther 2009;123: 143–50. Martin D, Lodge D. Ketamine acts as a non-competitive N-methyl-D-aspartate antagonist on frog spinal cord in vitro. Neuropharmacology 1985;24:999–1003. McKernan DP, Dinan TG, Cryan JF. Killing the Blues: a role for cellular suicide (apoptosis) in depression and the antidepressant response? Prog Neurobiol 2009;88:246–63. Muddashetty RS, Kelić S, Gross C, Xu Bassel GJ. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J Neurosci 2007;27:5338–48. Nemeroff CB, Owens MJ. Treatment of mood disorders. Nat Neurosci 2002;5:1068–70. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently over expressed in multiple myeloma cells and required for their survival. Cell 2009;137:873–86.
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Sarbassov D, Ali S, Kim D, Guertin D, Latek R, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296–302. Sarbassov D, Guertin D, Ali S, Sabatini D. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098–101. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter G, Holmes A, et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 1998;279:710–4. Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P, et al. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 2010;68:528–35. Warren BL, Iñiguez SD, Alcantara LF, Wright KN, Parise EM, Weakley SK, et al. Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood related stimuli and disrupts ventral tegmental area gene expression in adulthood. J Neurosci 2011;31:10347–58.
Wullschleger S, Loewith R, Hall MN. mTOR signaling in growth and metabolism. Cell 2006;124:471–84. Yang C, Li WY, Yu HY, Gao ZQ, Liu XL, Zhou ZQ, et al. Tramadol pretreatment enhances ketamine-induced antidepressant effects and increases mammalian target of rapamycin in rat hippocampus and prefrontal cortex. J Biomed Biotechnol 2012;2012:175619. Yang C, Zhou ZQ, Gao ZQ, Shi JY, Yang JJ. Acute increases in plasma Mammalian target of rapamycin, glycogen synthase kinase-3b, and eukaryotic elongation factor 2 phosphorylation after ketamine treatment in three depressed patients. Biol Psychiatry 2013;73:e35–6. Yu JJ, Zhang Y, Wang Y, Wen ZY, Liu XH, Qin J, et al. Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway. Psychopharmacology (Berl) 2013;225(2):361–72. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011;12(1):21–35.
Contents lists available at ScienceDirect
Life Sciences journal homepage: www.elsevier.com/locate/lifescie
Minireview
The role of mTOR in depression and antidepressant responses Helena M. Abelaira a, Gislaine Z. Réus a,b,⁎, Morgana V. Neotti a, João Quevedo a,b a b
Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA
a r t i c l e
i n f o
Article history: Received 10 October 2013 Accepted 14 February 2014 Available online 25 February 2014 Keywords: mTOR Antidepressants Ketamine Depression
a b s t r a c t The aim of this study was to characterize the mTOR signaling cascade in depression and the actions that antidepressant drugs have on this pathway. Herein, a literature review was performed by verification and comparison of textbooks and journal articles that describe the characterization of the mTOR signaling cascade and its relationship to depression and antidepressant drugs, especially ketamine. Postmortem studies have shown robust deficits in the mammalian target of rapamycin (mTOR) signaling in the prefrontal cortex of subjects diagnosed with major depressive disorder. However, besides the mTOR signaling pathway having an antidepressant response to various drugs, this seems to be more associated with antidepressant N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine. The characterization of the mTOR signaling pathway in depression and its action in response to antidepressants show great potential for the identification of new therapeutic targets for the development of antidepressant drugs. © 2014 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major depression . . . . . . . . . . . . . . . . . . . . . . . . . . mTOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The mTOR signaling cascade and its relationship with antidepressants Conclusions and future remarks . . . . . . . . . . . . . . . . . . .
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Conflicts of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Introduction Depression is a serious disorder that has enormous consequences for the quality of life, and is one of the most prevalent forms of mental illness (Larsen et al., 2010). It is a clinically and biologically heterogeneous disorder, with 10%–30% of women and 7%–15% of men likely to suffer from depression in their lifetime (Briley, 2000). Moreover, patients suffering from severe depression have high rates of morbidity and mortality, with profound economic and social consequences (Nemeroff and Owens, 2002). Serotonin and/or norepinephrine reuptake inhibitors are widely used to alleviate the symptoms
⁎ Corresponding author at: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil. Fax: +55 48 3431 2736. E-mail address: [email protected] (G.Z. Réus).
http://dx.doi.org/10.1016/j.lfs.2014.02.014 0024-3205/© 2014 Elsevier Inc. All rights reserved.
of depression in clinical practice. Unfortunately, the delayed onset time and the low remission rate of these conventional antidepressants are still major challenges (Machado-Vieira et al., 2009) Therefore, there is an urgent need to look for a fast-acting and effective antidepressant in the near future. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates the initiation of protein translation, and is expressed in dendritic development that controls new protein synthesis (Duman et al., 2012). Li et al (2010) have reported that the activation of mTOR in the prefrontal cortex underlies the antidepressant effects of ketamine in rats. Some case studies have also reported that mTOR is activated in depressed patients' peripheral blood after acute ketamine administration (Denk et al., 2011; Yang et al., 2013). In this case, the purpose of the present review is to offer an overview of the current knowledge about depression and the mTOR signaling pathway and the relationship that the mTOR signaling cascade has with depression and with antidepressants drugs.
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Major depression The mental disorder known as major depression is the most common mood disorder, affecting 5% of the population every year (Kessler and Wang, 2008; Lopez and Mathers, 2006). The main symptoms include depressed mood and diminished interest or pleasure in all activities. Other symptoms may also occur, including loss (or increase) in appetite, insomnia (or excessive sleep), fatigue, feelings of worthlessness and guilt, difficulty concentrating, and recurrent thoughts about death, among others (Krishnan and Nestler, 2008). Major depressive disorder (MDD) is currently treated with agents that increase neurotransmission monoaminergics, and the main monoamines that are related to depression are serotonin and/or noradrenaline. It is generally agreed that increased monoamine transmission initiates cellular adaptations that ultimately lead to therapeutic action (Warner-Schmidt et al., 2010). Identification and ultimately more direct targeting of these downstream mediators could lead to novel therapeutics that are both faster acting and produce fewer off-target effects. Treatment of depression is generally safe and effective but is far from ideal because the latency time for clinical benefit is relatively long (this period lasts between 3 and 5 weeks) and there are still major problems concerning side effects such as loss of libido and weight gain, among others. Although therapy for depression with drugs, psychotherapy and electroconvulsive therapy are effective, a significant number of patients do not respond well to these treatments (Anderson, 1996; Berton and Nestler, 2006). These findings suggest that adaptive changes in cellular signaling cascades (e.g., the brain-derived neurotrophic factor (BDNF)– TrkB receptor signaling pathway) may be responsible for the therapeutic effects of these drugs (Hashimoto, 2009; Lanni et al., 2009). Accumulating evidence suggests that psychotropic agents such as antidepressants realize their neurotrophic/neuroprotective effects by activating the mitogen-activated protein kinase (MAPK/ERK), phosphatidylinositol 3-kinase (PI3K), and glycogen synthase kinase 3 Wnt/GSK-3 signaling pathways. These agents also upregulate the expression of trophic/protective molecules such as BDNF, nerve growth factor (NGF), B-cell lymphoma 2 (Bcl-2), thymoma viral protooncogene (AKT) and BCL2-associated athanogene (BAG-1) and inactivate proapoptotic molecules such as GSK-3 (Hunsberger et al., 2009). However, in addition to this, Krishnan and Nestler (2008) and McKernan et al. (2009) demonstrated that BDNF and NGF activate
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signaling pathways involved in the upregulation of the expression of anti-apoptotic protein Bcl-2, B-cell lymphoma-extra large (Bcl-xl) and Bcl-2-associated x protein (Bax). Thus, it has been proposed that antidepressants elicit their effect by inducing the expression of neurotrophins while targeting apoptotic proteins at the same time, which results in blocking or even reversing apoptosis-induced structural alterations in limbic structures (McKernan et al., 2009; Banasr et al., 2011). mTOR The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, also known as a mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1), which modulates cell proliferation, mortality, survival and protein synthesis (Hay and Sonenberg, 2006). This serine/threonine kinase also belongs to the phosphatidylinositol 3-kinase-related kinase protein (PIKK) family. The mTOR pathway is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers (Beevers et al., 2006; Cornu et al., 2013; Zoncu et al., 2011). Human mTOR gene encodes a protein of 2549 amino acids with 42% and 45% sequence identity to yeast TOR1 and TOR2, respectively (Wullschleger et al., 2006). mTOR Complex 1 (mTORC1) is characterized by the classic features of mTOR by functioning as a nutrient/energy/ redox sensor and controlling protein synthesis (Kim et al., 2002). The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress (Kim et al., 2003) (Fig. 1). mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers; paxillin; ras homolog gene family, member A (RhoA); ras-related C3 botulinum toxin substrate 1 (Rac1); cell division cycle 42 (Cdc42); and protein kinase C α (PKCα) (Sarbassov et al., 2004). mTORC2 also appears to possess the activity of a previously elusive protein known as pyruvate dehydrogenase kinase isoform 2 (PDK2) and phosphorylates the serine/threonine protein kinase Akt/PKB at serine residue S473 (Sarbassov et al., 2005; Stephens et al., 1998) (Fig. 2). Both mTOR complexes are large, with mTORC1 having six and mTORC2 seven known protein components. They share the catalytic mTOR subunit and also mammalian lethal with sec-13 protein 8 (mLST8, also known as GbL) (Jacinto et al., 2004; Kim et al., 2003), DEP domain containing mTOR-interacting protein (DEPTOR) (Peterson
Fig. 1. mTORC1 complex. The mTORC1 complex responds to amino acids, oxidative stress, insulin, growth factors, serum and phosphatidic acid. mTORC1 promotes protein synthesis.
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Fig. 2. mTORC2 complex. The mTORC2 complex responds to growth factors and promotes the regulation of Akt/PKB, pyruvate dehydrogenase kinase isoform 2 (PDK2) and cytoskeleton through its stimulation of F-actin stress fibers; paxillin; ras homolog gene family, member A (RhoA); ras-related C3 botulinum toxin substrate 1 (Rac1); cell division cycle 42 (Cdc42); and protein kinase C α (PKCα).
et al., 2009), and the TELO2 interacting protein 1/telomere maintenance 2 (Tti1/Tel2) complex (Kaizuka et al., 2010). However, the mechanisms that activate or induce the mTOR signaling cascade are still unclear. The requirement for glutamate-AMPA (adhesion modulation protein A) receptor activation is consistent with the hypothesis that there is a subset of N-methyl-D-aspartate (NMDA) receptors, possibly on GABAergic interneurons, that when activated leads to disinhibition of glutamate signaling (Farber et al., 1998; Li et al., 2010). Thus, further characterization of these actions of NMDA receptor blockade and signaling pathways that stimulate mTOR signaling and mediate the rapid induction of synapses in the hippocampus, amygdala, prefrontal cortex and striatum will provide novel therapeutic targets for antidepressant drug development (Li et al., 2010). The mTOR signaling cascade and its relationship with antidepressants Many studies have highlighted the role of the NMDA receptor in depression. Accordingly, deficits in prominent postsynaptic proteins, including NMDA receptor subunits (NR2A and NR2B) and metabotropic glutamate receptor subtype 5 (mGlur5), were previously demonstrated in the prefrontal cortex from depressed subjects (Chandran et al., 2013; Deschwanden et al., 2011; Feyissa et al., 2009). Based on these studies, it is tempting to hypothesize that an activation of mTOR function followed by enhanced mTOR-dependent protein synthesis may underlie the action of antidepressants, such as ketamine (Chandran et al., 2013; Dwyer et al., 2012; Li et al., 2010, 2011). Ketamine is used clinically as a dissociative anesthetic (Martin and Lodge, 1985) and not only acts as an antagonist of the NMDA receptor, but it also interacts with channels and with voltage-sensitive Ca2+ opioid, monoamine and muscarinic receptors (Hirota and Lambert, 1996). Ketamine stimulation of mTOR signaling and antidepressant behavioral actions is dependent on glutamate-AMPA receptor activation (Duman et al., 2012). Drug targets that enhance glutamate transmission or activate AMPA receptors could also produce rapid and efficacious antidepressant action.
Recently, clinical observations have shown that sub-anesthetic doses of ketamine produce therapeutic effects in patients with depression (Berman et al., 2000; Correll and Futter, 2006). Postmortem studies showed robust deficits in mTOR signaling in the prefrontal cortex of subjects diagnosed with MDD (Chandran et al., 2013). Recent studies with animals indicate that the fast antidepressant response to NMDA receptor antagonists, such as ketamine, is mediated by rapid activation of the mTOR pathway leading to an increase in synaptic signaling proteins and an increased number and function of new spine synapses in the prefrontal cortex of rats (Li et al., 2010). Furthermore, Chandran et al. (2013) demonstrated that an eight-week chronic unpredictable stress (CUS) exposure produces deficits in the mTOR signaling pathway components in the amygdala. Moreover, it has been demonstrated that a single dose of ketamine rapidly reversed the chronic stress-induced behavior and synaptic deficits in an mTOR-dependent manner (Li et al., 2011). Hoeffer and Klann (2010) showed that ketamine produced a similar rapid and transient increase in the phosphorylated and activated forms of extracellular signal-regulated kinase (ERK, including ERK1 and ERK2) and protein kinase B (PKB/AKT) growth factor signaling pathways that have been linked to the activation of mTOR signaling. Still, Yu et al. (2013) showed that inhibition of mTOR by rapamycin reversed the antidepressant effects of ketamine in depressive patients. Nevertheless, unlike ketamine, other antidepressant treatment such as imipramine inhibited PI3K/Akt/mTOR signaling (Jeon et al., 2011). However, Warren et al. (2011) demonstrated that administration of fluoxetine in combination with methylphenidate induced mTOR activity in rats, and Lin et al. (2010) showed that sertraline exerts antiproliferative activity by targeting the mTOR signaling pathway in rat embryonic fibroblasts. Furthermore, besides the classic antidepressants, there are other drugs that have antidepressant effects and present an effect on mTOR signaling. Concomitant with this, Lauterbach (2012) demonstrated that dextromethorphan (DXM) directly influences mTOR signaling. DXM is an antitussive drug, but recently, the hypothesis was offered that DXM may have a potential as a rapidly acting antidepressant
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based on pharmacodynamic similarities to ketamine (Lauterbach, 2011). Yang et al. (2012) showed that pretreatment with tramadol enhanced the ketamine-induced antidepressant effects and upregulated the expression of mTOR in rat hippocampus and prefrontal cortex. Tramadol is a widely used analgesic agent, which exerts therapeutic effects via activation of opioid receptors and elevation of the plasma levels of serotonin and norepinephrine (Barber, 2011). As already mentioned, conventional antidepressants produce their effectiveness by increasing the level of monoamines, which share identical mechanisms of action to tramadol (Yang et al., 2012). However, unlike ketamine, these drugs have different effects on mTOR activity in the brain. These effects can be explained by the different mechanisms of action of these drugs, especially in the monoaminergic system. mTOR signaling activation by ketamine has been reported to be completely blocked by 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), an AMPA receptor antagonist. The mechanisms by which mGlu2/3 receptor antagonists activate mTOR signaling may be partly different from ketamine. Furthermore, stimulation of the AMPA receptor may be involved in the activation of mTOR signaling using mGLU2/3 receptor antagonists. This hypothesis is supported by Antion et al. (2008), who reported that the mGlu (mGlu1/5) receptor regulates mTOR signaling and that the mGlu1/5 receptor agonist, 3,5-dihydroxyphenylglycine, increased translation of synaptic related proteins, such as PSD-95, GluR1 and GluR2 in the cortex (Muddashetty et al., 2007). Conclusions and future remarks A number of studies have shown an association between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD. However, besides the mTOR signaling pathway having an antidepressant response to various drugs, this seems to be more associated with antidepressant NMDA receptor antagonists, such as ketamine. Thus, more studies are needed to characterize the mTOR signaling pathway in depression and their participation in antidepressant mechanisms. Further research will provide a great potential for the identification of new therapeutic targets for the development of antidepressant drugs. Conflicts of interest statement The authors have declared that no conflicts of interest exist relevant to the current manuscript.
Acknowledgments Laboratory of Neurosciences (Brazil) is a center within the National Institute for Translational Medicine (INCT-TM) and is also a member of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (JQ and GZR), FAPESC (JQ), Instituto Cérebro e Mente and UNESC (JQ). JQ is CNPq Research Fellows. GZR and HMA have CAPES studentships. References Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a attenuates the effects of antidepressants on the forced swim test in rats. Brain Res 1996;709:215–20. Antion MD, Hou L, Wong H, Hoeffer CA, Klann E. mGluR-dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of elongation factor 1A but remains expressed in S6K-deficient mice. Mol Cell Biol 2008;28:2996–3007. Banasr M, Dwyer JM, Duman RS. Cell atrophy and loss in depression: reversal by antidepressant treatment. Curr Opin Cell Biol 2011;23:730–7. Barber J. Examining the use of tramadol hydrochloride as an antidepressant. Exp Clin Psychopharmacol 2011;19:123–30. Beevers C, Li F, Liu L, Huang S. Curcumin inhibits the mammalian target of rapamycinmediated signaling pathways in cancer cells. Int J Cancer 2006;119:757–64. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47(4):351–4. Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006;7:137–51. Briley M, Moret C. Present and future anxiolytics. IDrugs 2000;3:695–9.
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Chandran A, Iyo AH, Jernigan CS, Legutko B, Austin MC, Karolewicz B. Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog Neuropsychopharmacol Biol Psychiatry 2013;40:240–5. Cornu M, Albert V, Hall MN. mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev 2013;23(1):53–62. Correll GE, Futter GE. Two case studies of patients with major depressive disorder given low-dose (subanesthetic) ketamine infusions. Pain Med 2006;7(1):92–5. Denk MC, Rewerts C, Holsboer F, Erhardt-Lehmann A, Turck CW. Monitoring ketamine treatment response in a depressed patient via peripheral mammalian target of rapamycin activation. Am J Psychiatry 2011;68(1):751–2. Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A, et al. Reduced metabotropic glutamate receptor 5 density in major depression determined by ABP688 PET and postmortem study. Am J Psychiatry 2011;168:727–34. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012;62:35–41. Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the antidepressant effects of mGluR2/3 blockade. Int J Neuropsychopharmacol 2012;15:429–34. Farber NB, Newcomer JW, Olney JW. The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer's disease. Prog Brain Res 1998;116:421–37. Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:70–5. Hashimoto K. Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 2009;6:105–23. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2006;18:1926–45. Hirota K, Lambert DJ. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth 1996;77:441–4. Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 2010;33:67–75. Hunsberger J, Austin DR, Henter ID, Chen G. The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues Clin Neurosci 2009;11:333–48. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6: 1122–8. Jeon SH, Kim Y, Kim YS, Lim Y, Lee YH, Shin SY. The tricyclic antidepressant imipramine induces autophagic cell death in U87MG gliom cells. Biochem Biophys Res Commun 2011;23:311–7. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, et al. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 2010;28:20109–16. Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu Rev Public Health 2008;29:115–29. Kim D, Sarbassov D, Ali S, King J, Latek R, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002:163–75. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003;11:895–904. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455: 894–902. Lanni C, Govoni S, Lucchelli A, Boselli C. Depression and antidepressants: molecular and cellular aspects. Cell Mol Life Sci 2009;66:2985–3008. Larsen MH, Mikkelsen JD, Hay-Schmidt A, Sandi C. Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment. J Psychiatr Res 2010;44:808–16. Lauterbach EC. Dextromethorphan as a potential rapid-acting antidepressant. Med Hypotheses 2011;76:717–9. Lauterbach EC. An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan. Med Hypotheses 2012;78:693–702. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;20:959–64. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011;69:754–61. Lin CJ, Robert F, Sukarieh R, Michnick S, Pelletier J. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Res 2010;15:3199–208. Lopez AD, Mathers CD. Measuring the global burden of disease and epidemiological transitions: 2002–2030. Ann Trop Med Parasitol 2006;100:481–99. Machado-Vieira R, Salvadore G, Diazgranados N, Zarate Jr CA. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther 2009;123: 143–50. Martin D, Lodge D. Ketamine acts as a non-competitive N-methyl-D-aspartate antagonist on frog spinal cord in vitro. Neuropharmacology 1985;24:999–1003. McKernan DP, Dinan TG, Cryan JF. Killing the Blues: a role for cellular suicide (apoptosis) in depression and the antidepressant response? Prog Neurobiol 2009;88:246–63. Muddashetty RS, Kelić S, Gross C, Xu Bassel GJ. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J Neurosci 2007;27:5338–48. Nemeroff CB, Owens MJ. Treatment of mood disorders. Nat Neurosci 2002;5:1068–70. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently over expressed in multiple myeloma cells and required for their survival. Cell 2009;137:873–86.
14
H.M. Abelaira et al. / Life Sciences 101 (2014) 10–14
Sarbassov D, Ali S, Kim D, Guertin D, Latek R, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296–302. Sarbassov D, Guertin D, Ali S, Sabatini D. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098–101. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter G, Holmes A, et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 1998;279:710–4. Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P, et al. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 2010;68:528–35. Warren BL, Iñiguez SD, Alcantara LF, Wright KN, Parise EM, Weakley SK, et al. Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood related stimuli and disrupts ventral tegmental area gene expression in adulthood. J Neurosci 2011;31:10347–58.
Wullschleger S, Loewith R, Hall MN. mTOR signaling in growth and metabolism. Cell 2006;124:471–84. Yang C, Li WY, Yu HY, Gao ZQ, Liu XL, Zhou ZQ, et al. Tramadol pretreatment enhances ketamine-induced antidepressant effects and increases mammalian target of rapamycin in rat hippocampus and prefrontal cortex. J Biomed Biotechnol 2012;2012:175619. Yang C, Zhou ZQ, Gao ZQ, Shi JY, Yang JJ. Acute increases in plasma Mammalian target of rapamycin, glycogen synthase kinase-3b, and eukaryotic elongation factor 2 phosphorylation after ketamine treatment in three depressed patients. Biol Psychiatry 2013;73:e35–6. Yu JJ, Zhang Y, Wang Y, Wen ZY, Liu XH, Qin J, et al. Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway. Psychopharmacology (Berl) 2013;225(2):361–72. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011;12(1):21–35.
