Neurochemical Research

, Volume 40, Issue 6, pp 1153–1164 | Cite as

Antidepressant Effects of Ketamine Are Not Related to 18F-FDG Metabolism or Tyrosine Hydroxylase Immunoreactivity in the Ventral Tegmental Area of Wistar Rats

  • Pedro Porto Alegre Baptista
  • Lisiani Saur
  • Pamela Bambrilla Bagatini
  • Samuel Greggio
  • Gianina Teribele Venturin
  • Sabrina Pereira Vaz
  • Kelly dos Reis Ferreira
  • Juliana Silva Junqueira
  • Diogo Rizzato Lara
  • Jaderson Costa DaCosta
  • Cristina Maria Moriguchi Jeckel
  • Régis Gemerasca Mestriner
  • Léder Leal Xavier
Original Paper


Major depressive disorder (MDD) is an important health problem that is often associated to stress. One of the main brain regions related to MDD is the ventral tegmental area (VTA), a dopaminergic center, part of the reward and motivation circuitry. Recent studies show that changes to VTA dopaminergic neurons are associated with depression and treatment. Ketamine has recently shown a fast, potent antidepressant effect in acute, sub-anesthetic doses. Thus, our aims were to elucidate if ketamine would be able to revert depression-like behaviors induced by a chronic unpredictable stress (CUS) protocol and if it could cause alterations to metabolism and tyrosine hydroxylase (TH)-immunoreactivity in VTA. For this, 48 Wistar rats were divided into four groups: control + saline (CTRL + SAL), control + ketamine (CTRL + KET), CUS + saline (CUS + SAL), CUS + ketamine (CUS + KET). The CUS groups underwent 28 days of CUS protocol. Saline or ketamine (10 mg/kg) was administered intraperitonially once on day 28. The behavior was assessed by the sucrose preference test, the open field test, and the forced swim test. Glucose brain metabolism was assessed and quantified with microPET. TH-immunoreactivity was assessed by estimating neuronal density and regional and cellular optical densities. A decrease in sucrose intake in the CUS groups and an increase in immobility was rapidly reverted by ketamine (p < 0.05). No difference was observed in the open field test. There was no alteration to VTA metabolism and TH-immunoreaction. These results suggest that the depressive-like behavior induced by CUS and the antidepressant effects of ketamine are unrelated to changes in neuronal metabolism or dopamine production in VTA.


Depression Ketamine MicroPET Tyrosine hydroxylase Ventral tegmental area 



The authors would like to thank the Brazilian funding agencies CNPq, CAPES, and FAPERGS for their support of this research. Dr. Diogo Lara, Dr. Jaderson Costa daCosta, and Dr. Léder Xavier are CNPq researchers.

Conflict of interest

The authors declare they have no conflicts of interest.


  1. 1.
    Agmo A, Galvan A, Talamentes B (1995) Reward and reinforcement produced by drinking sucrose: two processes that may depend on different neurotransmitters. Pharmacol Biochem Behav 52:403–414PubMedCrossRefGoogle Scholar
  2. 2.
    Ahmad A, Rasheed N, Banu N, Palit G (2010) Alterations in monoamine levels and oxidative systems in frontal cortex, striatum, and hippocampus of the rat brain during chronic unpredictable stress. Stress 13:355–364PubMedCrossRefGoogle Scholar
  3. 3.
    American Psychiatry Association (2014) Diagnostic and statistical manual of mental disorders: DSM-5, 1st edn. American Psychiatry Association, WashingtonGoogle Scholar
  4. 4.
    Bagatini PB, Xavier LL et al (2014) Resveratrol prevents akinesia and restores neuronal tyrosine hydroxylase immunoreactivity in the substancia nigra pars compact of diabetic rats. Brain Res 1592:101–112CrossRefGoogle Scholar
  5. 5.
    Banasr M, Valentine GW, Li X, Gourley SL, Taylor JR, Duman RS (2007) Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol Psychiatry 62:496–504PubMedCrossRefGoogle Scholar
  6. 6.
    Berman RM, Cappiello A et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354PubMedCrossRefGoogle Scholar
  7. 7.
    Bhutani MK, Bishnoi M, Kulkarni SK (2009) Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induce behavioral, biochemical and neurochemical chages. Pharmacol Biochem Behav 92:39–43PubMedCrossRefGoogle Scholar
  8. 8.
    Blood AJ, Iosifescu DV, Makris N, Perlis RH, Kennedy DN (2010) Microstuctural abnormalities in subcortical reward circuitry of subjects with major depressive disorder. PLoS One 5(11):e13945PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4:1–18CrossRefGoogle Scholar
  10. 10.
    Burgdorf J, Zhang X, Nicholson K et al (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38:729–742PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Cryan JF, Page ME, Lucki I (2005) Different behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology 182:335–344PubMedCrossRefGoogle Scholar
  12. 12.
    Czéh B, Simon M, Schmelting M, Hiemke C, Fuchs E (2006) Astroglial plasticity in the hippocampus of affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropharmacology 31:1616–1626Google Scholar
  13. 13.
    Dang H, Chen Y et al (2009) Antidepressant effects of gingseng total saponins in the forced swimming test and chronic mild stress models of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 33:1417–1424CrossRefGoogle Scholar
  14. 14.
    Diazgranados N, Ibrahim L et al (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67(8):793–802PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337PubMedCrossRefGoogle Scholar
  16. 16.
    Eisenstein SA, Clapper JR, Holmes PV, Piomelli D, Hohmann AG (2010) A role for 2-arachidonoyglycerol and endocannabinoid signaling in the locomotor response to novelty induced by olfactory bulbectomy. Pharmacol Res 61:419–429PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Ferrari AJ, Charlson FJ et al (2013) Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med 10(11):e1001547PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Ferraz AC, Matheussi F et al (2008) Evaluation of estrogen neuroprotective effect on nigrostriatal dopaminergic neurons following 6-hydroxydopamine injection into the substancia nigra pars compacta or the medial forebrain bundle. Neurochem Res 33:1238–1246PubMedCrossRefGoogle Scholar
  19. 19.
    Friedman AK, Walsh JJ et al (2014) Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 344:313–319PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Gunaydin LA, Grosenick L et al (2014) Natural neural projection dynamics underlying social behavior. Cell 157:1535–1551PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Hill MN, Hellemans KGC, Verma P, Gorzalka BB, Weinberg J (2012) Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav Rev 36:2085–2117PubMedCrossRefGoogle Scholar
  22. 22.
    Hnasko TS, Chuhma N et al (2010) Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65:643–656PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Hu H, Su L, Xu YQ, Zhang H, Wang LW (2010) Behavioral and [F-18] fluorodeoxyglucose micro positron emission tomography imaging study in a rat chronic mild stress model of depression. Neuroscience 169:171–181PubMedCrossRefGoogle Scholar
  24. 24.
    Huynh TN, Krigbaum AM, Hanna JJ, Conrad CD (2011) Sex difference and phase of light cycle modify chronic stress effects on anxiety and depressive-like behavior. Behav Brain Res 222:212–222PubMedCrossRefGoogle Scholar
  25. 25.
    Itoi K, Sugimoto N (2010) The brainstem noradrenergic systems in stress, anxiety and depression. J Neuroendocrinol 22:355–361PubMedCrossRefGoogle Scholar
  26. 26.
    Johnson BN, Yamamoto BK (2009) Chronic unpredictable stress augments +3,4-methylenedioxymethamphetamine-induced monoamine depletions: the role of corticosterone. Neuroscience 159:1233–1243PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Kristal JH, Sanacora G, Duman RS (2013) Rapid-actin glutamatergic antidepressant: the path to ketamine and beyond. Biol Psychiatry 73:1133–1141CrossRefGoogle Scholar
  29. 29.
    Lammel S, Lim BK, Malenka RC (2014) Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76:351–359PubMedCrossRefGoogle Scholar
  30. 30.
    Lang UE, Borgwardt S (2013) Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem 31:761–777PubMedCrossRefGoogle Scholar
  31. 31.
    Li N, Lee B et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Lin Z, Shi L et al (2013) Effects of curcumin on glucose metabolism in the brains of rats subjected to chronic unpredictable stress: a 18F-FDG micro-PET study. BMC Complem Alt Med 13:202CrossRefGoogle Scholar
  33. 33.
    Luckenbaugh DA, Niciu MJ et al (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord 159:56–61PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Ma X, Jiang D et al (2011) Social isolation-induced aggression potentiates anxiety and depressive-like behavior in male mice subjected to unpredictable chronic mild stress. PLoS One 6(6):e20955PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Ma XC, Dang YH, Jia M et al (2013) Long-lasting antidepressant action of ketamine, but noy glucogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice. PLoS One 8:e56053PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Machado-Vieira R, Manji HK, Zarate CA (2009) The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 15:525–539PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Maeng S, Zarate CA Jr, Du J et al (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63:349–352PubMedCrossRefGoogle Scholar
  38. 38.
    Matuszewich L, Karney JJ, Carter SR, Janasik SP, O’Brien JL, Friedman RD (2007) The delayed effects of chronic unpredictable stress on anxiety measures. Physiol Behav 90:674–681PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927PubMedGoogle Scholar
  40. 40.
    Morales M, Root DH (2014) Glutamate neurons within the midbrain dopamine regions. Neuroscience 282:60–68CrossRefGoogle Scholar
  41. 41.
    Murrough J, Charney DS (2011) Lifting the mood with ketamine. Nat Med 16(12):1384–1385CrossRefGoogle Scholar
  42. 42.
    Murrough JW, Iosifescu DV et al (2013) Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 170(10):1134–1142PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    do Nascimento PS, Lovatel GA et al (2011) Treadmill training improves motor skills and increases tyrosine hydroxylase immunoreactivity in the substancia nigra pars compacta in diabetic rats. Brain Res 1382:173–180PubMedCrossRefGoogle Scholar
  44. 44.
    Naughton M, Clarke G, O’Leary OF, Cryan JF, Dinan TG (2014) A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations and use and pre-clinical evidence on proposed mechanism of action. J Affect Disord 156:24–35PubMedCrossRefGoogle Scholar
  45. 45.
    Olfson M, Marcus SC, Shaffer D (2006) Antidepressant drug therapy and suicide in severely depressed children and adults. Arch Gen Psychiatry 63:865–872PubMedCrossRefGoogle Scholar
  46. 46.
    Ortiz J, Fitzgerald LW, Lane S, Terwillinger R, Nestler EJ (1996) Biochemical adaptations in the mesolimbic dopamine system in response to repeated stress. Neuropsychopharmacology 14:443–452PubMedCrossRefGoogle Scholar
  47. 47.
    Otte D-M, Barcena de Arellano ML et al (2013) Effects of chronic d-serine elevation on animal models of depression and anxiety-related behavior. PLoS One 8(6):e67131PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Polter AM, Kauer JA (2014) Stress and VTA synapses: implications for addiction and depression. Eur J Neurosci 39:1179–1188PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Price RB, Nock MK, Charney DS, Mathew SJ (2009) Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 66:522–526PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Quan M, Zhang N, Wang Y, Zhang T, Yang Z (2011) Possible antidepressant effects and mechanisms of memantine in behaviors and synaptic plasticity of a depression rat model. Neuroscience 182:88–97PubMedCrossRefGoogle Scholar
  51. 51.
    Rasheed N, Ahmad A, Pandey CP, Chatuverdi RK, Lohani M, Palit G (2010) Differential response of central dopaminergic system in acute and chronic unpredictable stress model in rats. Neurochem Res 35:22–32PubMedCrossRefGoogle Scholar
  52. 52.
    Rasheed N, Tyagi E, Ahmad A, Siripurapu KB, Lahiri S, Shukla R, Palit G (2008) Involvement of monoamines and proinflammatory cytokines in mediating the anti-stress effects of Panax quinquefolium. J Ethnopharmacol 117:257–262PubMedCrossRefGoogle Scholar
  53. 53.
    Razafsha M, Behforuzi H et al (2013) An updated overview of animal models in neuropsychiatry. Neuroscience 240:204–218PubMedCrossRefGoogle Scholar
  54. 54.
    Rizelio V, Szawka RE et al (2010) Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neuronsin a rat 6-hydroxydopamine-lesion model of Parkinson’s disease. Braz J Med Biol Res 43(1):85–95PubMedCrossRefGoogle Scholar
  55. 55.
    Rong H, Wang G, Liu T, Wang H, Wan Q, Weng S (2010) Chronic mild stress induces fluoxetine-reversible decreases in hippocampal and cerebrospinal fluid levels of the neurotrophic factor S100B and its specific receptor. Int J Mol Sci 11:5310–5322PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Saur L, Baptista PPA et al (2014) Physical exercise increases GFAP expression and induces morphological changes in hippocampal astrocytes. Brain Struct Funct 219:293–302PubMedCrossRefGoogle Scholar
  57. 57.
    Slattery DA, Cryan JF (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc 7(6):1009–1014PubMedCrossRefGoogle Scholar
  58. 58.
    Schiffer WK, Mirrione MM et al (2006) Serial microPET measures of the metabolic reaction to a microdialysis probe implat. J Neurosci Methods 155:272–284PubMedCrossRefGoogle Scholar
  59. 59.
    Su X, Cheng K (2014). Comparison of two site-specifically 18F-labelled affibodies for PET imaging of EGFR positive tumors. Mol Pharm 11(11):3947–3956PubMedCrossRefGoogle Scholar
  60. 60.
    Tata DA, Yamamoto BK (2008) Chronic stress enhances methamphetamine-induced extracellular glutamate and excitotoxicity in the rat striatum. Synapse 62:325–336PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Tye KM, Mirzabekov JJ et al (2013) Dopamine neurons modulate neural encoding and expression of depression-related behavior. Nature 493:537–541PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Uher R, Payne JL, Pavlova B, Perlis RH (2014) Major depressive disorder in DSM-5: implications for clinical practice and research of changes from DSM-IV. Depress Anxiety 31:459–471PubMedCrossRefGoogle Scholar
  63. 63.
    Venzala E, García-García AL, Elizalde N, Tordera RM (2013) Social vs. environmental stress model of depression from a behavioural and neurochemical approach. Eur Neuropsychopharmacol 23:697–708PubMedCrossRefGoogle Scholar
  64. 64.
    WHO (2012) Depression: a global crisis. World Federation for Mental Health, Occoquan, VAGoogle Scholar
  65. 65.
    Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110PubMedCrossRefGoogle Scholar
  66. 66.
    Willner P, Scheel-Kruger J, Belzung C (2013) The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev 37:2331–2371PubMedCrossRefGoogle Scholar
  67. 67.
    Winter C, von Rumohr A et al (2007) Lesions of dopaminergic neurons in the substancia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats. Behav Brain Res 184:133–141PubMedCrossRefGoogle Scholar
  68. 68.
    Wyckhuys T, Wyffels L, Langlois X, Schmidt M, Stroobants S, Staelens S (2014) The [18F] FDG µPET readout of a brain activation model to evaluate the metabotropic glutamate receptor 2 positive allosteric modulator JNJ-42153605. J Pharmacol Exp Ther 350(2):375–386PubMedCrossRefGoogle Scholar
  69. 69.
    Xavier LL, Viola GG et al (2005) A simple and fast densitometric method for the analysis of tyrosine hydroxylase immunoreactivity in the substancia nigra pars compacta and in the ventral tegmental area. Brain Res Protoc 16:58–64CrossRefGoogle Scholar
  70. 70.
    Yang C, Li X, Wang N et al (2012) Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in rat hippocampus. Front Med 6:411–415PubMedCrossRefGoogle Scholar
  71. 71.
    Yang C, Hu YM, Zhou ZQ et al (2013) Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test. Ups J Med Sci 118:3–8PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Yi LT, Li JM, Li YC, Pan Y, Xu Q, Kong LD (2008) Antidepressant-like behavioral and neurochemical effects of the citrus-associated chemical apigenin. Life Sci 82:741–751PubMedCrossRefGoogle Scholar
  73. 73.
    Zarate CA Jr, Singh JB et al (2006) A randomized trial of N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864PubMedCrossRefGoogle Scholar
  74. 74.
    Zhong P, Liu X et al (2014) Cyclin-dependent kinase 5 in the ventral tegmental area regulates depression-related behaviors. J Neurosci 34(18):6352–6366PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Zhu MY, Klimek V et al (1999) Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry 46(9):1275–1286PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Pedro Porto Alegre Baptista
    • 1
  • Lisiani Saur
    • 1
  • Pamela Bambrilla Bagatini
    • 1
  • Samuel Greggio
    • 2
  • Gianina Teribele Venturin
    • 2
  • Sabrina Pereira Vaz
    • 1
  • Kelly dos Reis Ferreira
    • 1
  • Juliana Silva Junqueira
    • 1
  • Diogo Rizzato Lara
    • 1
  • Jaderson Costa DaCosta
    • 2
  • Cristina Maria Moriguchi Jeckel
    • 2
  • Régis Gemerasca Mestriner
    • 1
  • Léder Leal Xavier
    • 1
    • 2
  1. 1.Laboratório de Biologia Celular e Tecidual e Laboratório de Neuroquímica e Psicofarmacologia, Departamento de Ciências Morfofisiológicas, Faculdade de BiociênciasPontifícia Universidade Católica do Rio Grande do Sul (PUCRS)Porto AlegreBrazil
  2. 2.Centro de Pesquisa Pré-Clínica e Centro de Produção de RadiofármacosInstituto do Cérebro do Rio Grande do Sul – INSCER-PUCRSPorto AlegreBrazil

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