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Treatment with tianeptine induces antidepressive-like effects and alters the neurotrophin levels, mitochondrial respiratory chain and cycle Krebs enzymes in the brain of maternally deprived adult rats

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Abstract

Maternally deprived rats were treated with tianeptine (15 mg/kg) once a day for 14 days during their adult phase. Their behavior was then assessed using the forced swimming and open field tests. The BDNF, NGF and energy metabolism were assessed in the rat brain. Deprived rats increased the immobility time, but tianeptine reversed this effect and increased the swimming time; the BDNF levels were decreased in the amygdala of the deprived rats treated with saline and the BDNF levels were decreased in the nucleus accumbens within all groups; the NGF was found to have decreased in the hippocampus, amygdala and nucleus accumbens of the deprived rats; citrate synthase was increased in the hippocampus of non-deprived rats treated with tianeptine and the creatine kinase was decreased in the hippocampus and amygdala of the deprived rats; the mitochondrial complex I and II–III were inhibited, and tianeptine increased the mitochondrial complex II and IV in the hippocampus of the non-deprived rats; the succinate dehydrogenase was increased in the hippocampus of non-deprived rats treated with tianeptine. So, tianeptine showed antidepressant effects conducted on maternally deprived rats, and this can be attributed to its action on the neurochemical pathways related to depression.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

NGF:

Nerve growth factor

References

  • Abelaira HM, Réus GZ, Ribeiro KF, Zappellini G, Ferreira GK, Gomes LM, Carvalho-Silva M, Luciano TF, Marques SO, Streck EL, Souza CT, Quevedo J (2011) Effects of acute and chronic treatment elicited by lamotrigine on behavior, energy metabolism, neurotrophins and signaling cascades in rats. Neurochem Int 59:1163–1174

    Article  PubMed  CAS  Google Scholar 

  • Abelaira HM, Réus GZ, Ribeiro KF, Zappellin G, Cipriano AL, Scaini G, Streck EL, Quevedo J (2012) Lamotrigine treatment reverses depressive-like behavior and alters BDNF levels in the brains of maternally deprived adult rats. Pharmacol Biochem Behav 101:348–353

    Article  PubMed  CAS  Google Scholar 

  • Aisa B, Tordera R, Lasheras B, Del Río J, Ramírez MJ (2007) Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats. Psychoneuroendocrinol 32:256–266

    Article  CAS  Google Scholar 

  • Anisman H, Zaharia MD, Meaney MJ, Merali Z (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci 16:149–164

    Google Scholar 

  • Assis LC, Rezin GT, Comim CM, Valvassori SS, Jeremias IC, Zugno AI, Quevedo J, Streck EL (2009) Effect of acute administration of ketamine and imipramine on creatine kinase activity in the brain of rats. Rev Bras Psiquiatr 31:247–252

    Article  PubMed  Google Scholar 

  • Cassina A, Radi R (1996) Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 328:309–316

    Article  PubMed  CAS  Google Scholar 

  • Castanon N, Konsman JP, Médina C, Chauvet N, Dantzer R (2003) Chronic treatment with the antidepressant tianeptine attenuates lipopolysaccharide-induced Fos expression in the rat paraventricular nucleus and HPA axis activation. Psychoneuroendocrinol 28:19–34

    Google Scholar 

  • Cheng B, Mattson MP (1994) NT-3 and BDNF protect CNS neurons against metabolicrexcitotoxic insults. Brain Res 640:56–67

    Article  PubMed  CAS  Google Scholar 

  • Conrad CD, LeDoux JE, Magariños AM, McEwen BS (1999) Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci 113:902–913

    Article  PubMed  CAS  Google Scholar 

  • Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A 98:12796–12801

    Article  PubMed  CAS  Google Scholar 

  • D’sa C, Duman RS (2002) Antidepressants and neuroplasticity. Bipolar Disord 4:183–194

    Article  PubMed  Google Scholar 

  • Darley-Usmar VM, Hogg H, O’Learly VJ, Wilson MT, Moncada S (1992) The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Rad Res Commun 17:9–20

    Article  CAS  Google Scholar 

  • Davey GP, Clark JB (1996) Threshold effects and control of oxidative phosphorilation in nonsynaptic rat brain mitochondria. Neurochem 66:1617–1624

    Article  CAS  Google Scholar 

  • Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacol 121:66–72

    Article  CAS  Google Scholar 

  • Duman RS, Nakagawa S, Malberg J (2001) Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacol 25:836–844

    Google Scholar 

  • Ecklund MB, Arborelius L (2006) Twice daily long maternal separations in Wistar rats decreases anxiety-like behaviour in females but does not affect males. Behav Brain Res 172:278–285

    Article  Google Scholar 

  • Eisch AJ, Bolanos CA, de Wit J, Simonak RD, Pudiak CM, Barrot M, Verhaagen J, Nestler EJ (2003) Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry 54:994–1005

    Article  PubMed  CAS  Google Scholar 

  • El Hage M, Baverel G, Martin G (2006) Effects of valproate on glutamate metabolism in rat brain slices: A CNMR study. Epilepsy Res.

  • El Khoury A, Gruber SH, Mørk A, Mathé AA (2006) Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Progr Neuropsychopharmacol Biol Psychiatry 30:535–540

    Article  Google Scholar 

  • Fattal O, Link J, Quinn K, Cohen BH, Franco K (2007) Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectr 12:429–438

    PubMed  Google Scholar 

  • Fischer JC, Ruitenbeek W, Berden JA, Trijbels JM, Veerkamp JH, Stadhouders AM, Sengers RC, Janssen AJ (1995) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36

    Article  Google Scholar 

  • Francis PT, Poynton A, Lowe SL, Najlerahim A, Bridges PK, Bartlett JR, Procter AW, Bruton CJ, Bowen DM (1999) Brain amino acid concentrations and Ca2+ dependent release in intractable depression assessed antemortem. Brain Res 494:315–324

    Google Scholar 

  • Garcia LS, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J (2008a) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Progr Neuropsychopharmacol Biol Psychiatry 32:140–144

    Article  CAS  Google Scholar 

  • Garcia LS, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J (2008b) Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels. Basic Clin Pharmacol and Toxicol 103:502–506

    Article  CAS  Google Scholar 

  • Gardner A, Johansson A, Wibom R et al (2003) Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J Affect Disord 76:55–68

    Article  PubMed  CAS  Google Scholar 

  • Gardner A, Salmaso D, Nardo D, Micucci F, Nobili F, Sanchez-Crespo A, Jacobsson H, Larsson SA, Pagani M (2008) Mitochondrial function is related to alterations at brain SPECT in depressed patients. CNS Spectrums 13:805–814

    PubMed  Google Scholar 

  • Gildengers AG, Whyte EM, Drayer RA, Soreca I, Fagiolini A, Kilbourne AM, Houck PR, Reynolds CF 3rd, Frank E, Kupfer DJ, Mulsant BH (2008) Medical burden in late-life bipolar and major depressive disorders. Am J Geriatr Psychiatry 16:194–200

    Article  PubMed  Google Scholar 

  • Grimm JW, Lu Hayashi T, Hope BT, Su TP, Shaham Y (2003) Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23:742–747

    PubMed  CAS  Google Scholar 

  • Hellweg R, Lang UE, Nagel M, Baumgartner A (2002) Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats. Mol Psychiatry 7:604–608

    Article  PubMed  CAS  Google Scholar 

  • Hennessy MB, Deak T, Schiml-Webb PA (2001) Stress induced sickness behaviors: an alternative hypothesis for responses during maternal separation. Develop Psychobiol 39:76–83

    Article  CAS  Google Scholar 

  • Horger BA, Iyasere CA, Berhow MT, Messer CJ, Nestler EJ, Taylor JR (1999) Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J Neurosci 19:4110–4122

    PubMed  CAS  Google Scholar 

  • Hughes BP (1962) A method for estimation of serum creatine kinase and its use in comparing creatine kinase and aldolase activity in normal and pathologic sera. Clin Chim Acta 7:597–604

    Article  PubMed  CAS  Google Scholar 

  • Jain R (2009) The epidemiology and recognition of pain and physical symptoms in depression. J Clin Psychiatry. doi:10.4088/JCP.8001tx1c.e04

  • Kitto GB (1969) Intra- and extramitochondrial malate dehydrogenases from chicken and tuna heart. Methods Enzymol 13:106–116

    Article  CAS  Google Scholar 

  • Kokaia Z, Bengzon J, Metsis M, Kokaia Persson H, Lindvall O (1993) Coexpression of neurotrophins and their receptors in neurons of the central nervous system. Proc Natl Acad Sci USA 90:6711–6715

    Article  PubMed  CAS  Google Scholar 

  • Kosten TA, Lee HJ, Kim JJ (2007) Neonatal handling alters learning in adult male and female rats in a task-specific manner. Brain Res 18:144–153

    Article  Google Scholar 

  • Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902

    Article  PubMed  CAS  Google Scholar 

  • Kuroda Y, McEwen BS (1998) Effect of chronic restraint stress and tianeptine on growth factors, growth-associated protein-43 and microtubule-associated protein 2 mRNA expression in the rat hippocampus. Brain Res Mol Brain Res 59:35–39

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Madrigal JL, Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Rodrigo J, Leza JC (2001) Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacol 24:420–429

    Article  CAS  Google Scholar 

  • Magarinos AM, Deslandes A, Mcewen BS (1999) Effects of antide pressants and benzodiazepine treatments on the dendritic structure CA3 pyramidal neurons after chronic stress. Eur J Pharmacol 371:113–122

    Article  PubMed  CAS  Google Scholar 

  • Mello PB (2009) Physical exercise can reverse the deficit in fear memory induced by maternal deprivation. Neurobiol Learn and Memory 92:364–369

    Article  Google Scholar 

  • Morley-Fletcher S, Darnaudery M, Koehl M, Casolini P, Van Reeth O, Maccari S (2003) Prenatal stress in rats predicts immobility behavior in the forced swim test, effects of a chronic treatment with tianeptine. Brain Res 989:246–251

    Article  PubMed  CAS  Google Scholar 

  • Narita M, Aoki K, Takag M, Yajima Y, Suzuki T (2003) Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine. Neurosci 119:767–775

    Article  CAS  Google Scholar 

  • Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 3:13–25

    Article  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain: stereotaxic coordinates, Secondth edn. Academic, Australia

    Google Scholar 

  • Petrovich GD, Holland PC, Gallagher M (2005) Amygdalar and prefrontal pathways to the lateral hypothalamus are activated by a learned cue that stimulates eating. J Neurosci 25:8295–8302

    Article  PubMed  CAS  Google Scholar 

  • Pitra P, Tokarski K, Grzegorzewska M, Hess G (2007) Effects of repetitive administration of tianeptine, zinc hydroaspartate and electroconvulsive shock on the reactivity of 5-HT(7) receptors in rat hippocampus. Pharmacol Reviews 59:627–635

    CAS  Google Scholar 

  • Plotsky PM, Meaney MJ (1993) Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res 18:195–200

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Animal model of depression. Nature 266:730–732

    Article  PubMed  CAS  Google Scholar 

  • Pryce CR, Feldon J (2003) Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci BiobehavReview 27:57–71

    Article  Google Scholar 

  • Radi R, Beckman JS, Bush KM, Freeman BA (1991a) Peroxynitrite- induced membrane lipid peroxidation: the cytocoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288:481–487

    Article  PubMed  CAS  Google Scholar 

  • Radi R, Beckman JS, Bush KM, Freeman BA (1991b) Peroxynitrite oxidation of sulfhydryls. The citotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250

    PubMed  CAS  Google Scholar 

  • Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC et al (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098

    Article  PubMed  CAS  Google Scholar 

  • Reagan LP, Hendry RM, Reznikov LR et al (2007) Tianeptine increases brain-derived neurotrophic factor expression in the rat amygdala. Eur J Pharmacol 565:68–75

    Article  PubMed  CAS  Google Scholar 

  • Réus GZ, Stringari RB, Ribeiro KF, Cipriano AL, Panizzutti BS, Stertz L, Lersch C, Kapczinski F, Quevedo J (2011) Maternal deprivation induces depressive-like behaviour and alters neurotrophin levels in the rat brain. Neurochem Res 363:460–466

    Article  Google Scholar 

  • Rezin GT, Cardoso MR, Gonçalves CL, Scaini G, Fraga DB, Riegel RE, Comim CM, Quevedo J, Streck EL (2008) Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem Int 53:395–400

    Article  PubMed  CAS  Google Scholar 

  • Ruedi-Bettschen D (2006) Early deprivation leads to altered behavioural, autonomic and endocrine responses to environmental challenge in adult Fischer rats. Eur J Neurosci 24:2879–2979

    Article  PubMed  Google Scholar 

  • Rustin P, Munnich A, Rotig A (2002) Succinate dehydrogenase and human diseases: newinsights into a well-known enzyme. Eur J Hum Gen 10:289–291

    Article  CAS  Google Scholar 

  • Santos PM, Scaini G, Rezin GT, Benedet J, Rochi N, Jeremias GC, Carvalho-Silva M, Quevedo J, Streck EL (2009) Brain creatine kinase activity is increased by chronic administration of paroxetine. Brain Res Bull 80:327–330

    Article  PubMed  CAS  Google Scholar 

  • Scaini G, Santos PM, Benedet J, Rochi N, Gomes LM, Borges LS, Rezin GT, Pezente DP, Quevedo J, Streck EL (2010) Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants. Brain Res Bull 82:224–227

    Article  PubMed  CAS  Google Scholar 

  • Schulte-Herbrüggen O, Chourbaji S, Müller H, Danker-Hopfe H, Brandwein C, Gass P, Hellweg R (2006) Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness. Experimental Neurol 202:404–409

    Article  Google Scholar 

  • Schulte-Herbrüggen O, Fuchs E, Abumaria N, Ziegler A, Danker-Hopfe H, Hiemke C, Hellweg R (2009) Effects of escitalopram on the regulation of brain-derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress. J Neurosci Res 8711:2551–2260

    Article  Google Scholar 

  • Shirayama Y, Chaki S (2006) Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents. Curr Neuropharmacol 4:277–291

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777

    PubMed  CAS  Google Scholar 

  • Solich J, Pałach P, Budziszewska B, Dziedzicka-Wasylewska M (2008) Effect of two behavioral tests on corticosterone level in plasma of mice lacking the noradrenaline transporter. Pharmacol Reviews 60:1008–1013

    CAS  Google Scholar 

  • Srere PA (1969) Citrate synthase. In: Lowenstein JM (ed) Methods in enzymology, citric acid cycle. Academic, New York, pp 3–11

    Chapter  Google Scholar 

  • Tanabe K, Masuda K, Hirayama A, Nagase S, Kono I, Kuno S (2006) Effect of spontaneous exercise on antioxidant capacity in rat muscles determined by electron spin resonance. Acta Physiol 186:119–125

    Article  CAS  Google Scholar 

  • Ueyama Y, Kawai K, Nemoto M, Sekimoto S, Tone E (1997) Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain. Neurosci Res 28:103–110

    Article  PubMed  CAS  Google Scholar 

  • Uzbay TI (2008) Tianeptine: potential influences on neuroplasticity and novel pharmacological effects. Prog Neuropsychopharmacol Biol Psychiatry 32:915–924

    Google Scholar 

  • Uzbekov MG, Misionzhnik EY, Maximova NM, Vertogradova OP (2006) Biochemical profile in patients with anxious depression under the treatment with serotonergic antidepressants with different mechanisms of action. Hum Psychopharmacol 21:109–115

    Article  PubMed  CAS  Google Scholar 

  • Wilde MI, Benfield P (1995) Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression. Drugs 49:411–439

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported in part by grants from ‘Conselho Nacional de Desenvolvimento Científico e Tecnológico’ (CNPq-Brazil – JQ, FDP and FK), from ‘Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina’ (FAPESC-Brazil - JQ and FDP), from the Instituto Cérebro e Mente (JQ) and UNESC (JQ and FDP). JQ, FK and FDP are recipients of CNPq (Brazil) Productivity Fellowships. GZR is holder of a CAPES studentship.

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  1. Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil

    Franciela P. Della, Helena M. Abelaira, Gislaine Z. Réus, Maria Augusta B. dos Santos, Débora B. Tomaz, Altamir R. Antunes & João Quevedo

  2. Laboratório de Bioenergética and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil

    Giselli Scaini, Meline O. S. Morais & Emilio L. Streck

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  1. Franciela P. Della
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  2. Helena M. Abelaira
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Correspondence to Gislaine Z. Réus.

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Della, F.P., Abelaira, H.M., Réus, G.Z. et al. Treatment with tianeptine induces antidepressive-like effects and alters the neurotrophin levels, mitochondrial respiratory chain and cycle Krebs enzymes in the brain of maternally deprived adult rats. Metab Brain Dis 28, 93–105 (2013). https://doi.org/10.1007/s11011-012-9375-x

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