Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  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 52:403–414

    Article  CAS  PubMed  Google Scholar 

  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 13:355–364

    Article  PubMed  Google Scholar 

  3. American Psychiatry Association (2014) Diagnostic and statistical manual of mental disorders: DSM-5, 1st edn. American Psychiatry Association, Washington

    Google Scholar 

  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 1592:101–112

    Article  CAS  Google Scholar 

  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 62:496–504

    Article  CAS  PubMed  Google Scholar 

  6. Berman RM, Cappiello A et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354

    Article  CAS  PubMed  Google Scholar 

  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 92:39–43

    Article  CAS  PubMed  Google Scholar 

  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):e13945

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4:1–18

    Article  Google Scholar 

  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 38:729–742

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 182:335–344

    Article  CAS  PubMed  Google Scholar 

  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 31:1616–1626

    Google Scholar 

  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 33:1417–1424

    Article  CAS  Google Scholar 

  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):793–802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337

    Article  CAS  PubMed  Google Scholar 

  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 61:419–429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):e1001547

    Article  PubMed Central  PubMed  Google Scholar 

  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 33:1238–1246

    Article  CAS  PubMed  Google Scholar 

  19. Friedman AK, Walsh JJ et al (2014) Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 344:313–319

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Gunaydin LA, Grosenick L et al (2014) Natural neural projection dynamics underlying social behavior. Cell 157:1535–1551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Hill MN, Hellemans KGC, Verma P, Gorzalka BB, Weinberg J (2012) Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav Rev 36:2085–2117

    Article  CAS  PubMed  Google Scholar 

  22. Hnasko TS, Chuhma N et al (2010) Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65:643–656

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 169:171–181

    Article  CAS  PubMed  Google Scholar 

  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 222:212–222

    Article  PubMed  Google Scholar 

  25. Itoi K, Sugimoto N (2010) The brainstem noradrenergic systems in stress, anxiety and depression. J Neuroendocrinol 22:355–361

    Article  CAS  PubMed  Google Scholar 

  26. Johnson BN, Yamamoto BK (2009) Chronic unpredictable stress augments +3,4-methylenedioxymethamphetamine-induced monoamine depletions: the role of corticosterone. Neuroscience 159:1233–1243

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kristal JH, Sanacora G, Duman RS (2013) Rapid-actin glutamatergic antidepressant: the path to ketamine and beyond. Biol Psychiatry 73:1133–1141

    Article  Google Scholar 

  29. Lammel S, Lim BK, Malenka RC (2014) Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76:351–359

    Article  CAS  PubMed  Google Scholar 

  30. Lang UE, Borgwardt S (2013) Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem 31:761–777

    Article  CAS  PubMed  Google Scholar 

  31. Li N, Lee B et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 13:202

    Article  Google Scholar 

  33. Luckenbaugh DA, Niciu MJ et al (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord 159:56–61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):e20955

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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:e56053

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 15:525–539

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 63:349–352

    Article  CAS  PubMed  Google Scholar 

  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 90:674–681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 17:2921–2927

    CAS  PubMed  Google Scholar 

  40. Morales M, Root DH (2014) Glutamate neurons within the midbrain dopamine regions. Neuroscience 282:60–68

    Article  CAS  Google Scholar 

  41. Murrough J, Charney DS (2011) Lifting the mood with ketamine. Nat Med 16(12):1384–1385

    Article  Google Scholar 

  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):1134–1142

    Article  PubMed Central  PubMed  Google Scholar 

  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 1382:173–180

    Article  PubMed  Google Scholar 

  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 156:24–35

    Article  CAS  PubMed  Google Scholar 

  45. Olfson M, Marcus SC, Shaffer D (2006) Antidepressant drug therapy and suicide in severely depressed children and adults. Arch Gen Psychiatry 63:865–872

    Article  PubMed  Google Scholar 

  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 14:443–452

    Article  CAS  PubMed  Google Scholar 

  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):e67131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Polter AM, Kauer JA (2014) Stress and VTA synapses: implications for addiction and depression. Eur J Neurosci 39:1179–1188

    Article  PubMed Central  PubMed  Google Scholar 

  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 66:522–526

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 182:88–97

    Article  CAS  PubMed  Google Scholar 

  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 35:22–32

    Article  CAS  PubMed  Google Scholar 

  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 117:257–262

    Article  CAS  PubMed  Google Scholar 

  53. Razafsha M, Behforuzi H et al (2013) An updated overview of animal models in neuropsychiatry. Neuroscience 240:204–218

    Article  CAS  PubMed  Google Scholar 

  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):85–95

    Article  CAS  PubMed  Google Scholar 

  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 11:5310–5322

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Saur L, Baptista PPA et al (2014) Physical exercise increases GFAP expression and induces morphological changes in hippocampal astrocytes. Brain Struct Funct 219:293–302

    Article  CAS  PubMed  Google Scholar 

  57. Slattery DA, Cryan JF (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc 7(6):1009–1014

    Article  CAS  PubMed  Google Scholar 

  58. Schiffer WK, Mirrione MM et al (2006) Serial microPET measures of the metabolic reaction to a microdialysis probe implat. J Neurosci Methods 155:272–284

    Article  CAS  PubMed  Google Scholar 

  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):3947–3956

    Article  CAS  PubMed  Google Scholar 

  60. Tata DA, Yamamoto BK (2008) Chronic stress enhances methamphetamine-induced extracellular glutamate and excitotoxicity in the rat striatum. Synapse 62:325–336

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Tye KM, Mirzabekov JJ et al (2013) Dopamine neurons modulate neural encoding and expression of depression-related behavior. Nature 493:537–541

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 31:459–471

    Article  PubMed  Google Scholar 

  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 23:697–708

    Article  CAS  PubMed  Google Scholar 

  64. WHO (2012) Depression: a global crisis. World Federation for Mental Health, Occoquan, VA

    Google Scholar 

  65. Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110

    Article  CAS  PubMed  Google Scholar 

  66. Willner P, Scheel-Kruger J, Belzung C (2013) The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev 37:2331–2371

    Article  CAS  PubMed  Google Scholar 

  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 184:133–141

    Article  CAS  PubMed  Google Scholar 

  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):375–386

    Article  PubMed  Google Scholar 

  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 16:58–64

    Article  CAS  Google Scholar 

  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 6:411–415

    Article  PubMed  Google Scholar 

  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 118:3–8

    Article  PubMed Central  PubMed  Google Scholar 

  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 82:741–751

    Article  CAS  PubMed  Google Scholar 

  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):856–864

    Article  CAS  PubMed  Google Scholar 

  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):6352–6366

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Zhu MY, Klimek V et al (1999) Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry 46(9):1275–1286

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Laboratório de Biologia Celular e Tecidual e Laboratório de Neuroquímica e Psicofarmacologia, Departamento de Ciências Morfofisiológicas, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Prédio 12, Sala 104, Porto Alegre, RS, CEP 90619-900, Brazil

    Pedro Porto Alegre Baptista, Lisiani Saur, Pamela Bambrilla Bagatini, Sabrina Pereira Vaz, Kelly dos Reis Ferreira, Juliana Silva Junqueira, Diogo Rizzato Lara, Régis Gemerasca Mestriner & Léder Leal Xavier

  2. Centro de Pesquisa Pré-Clínica e Centro de Produção de Radiofármacos, Instituto do Cérebro do Rio Grande do Sul – INSCER-PUCRS, Porto Alegre, Brazil

    Samuel Greggio, Gianina Teribele Venturin, Jaderson Costa DaCosta, Cristina Maria Moriguchi Jeckel & Léder Leal Xavier

Authors
  1. Pedro Porto Alegre Baptista
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisiani Saur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pamela Bambrilla Bagatini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samuel Greggio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gianina Teribele Venturin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sabrina Pereira Vaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kelly dos Reis Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Juliana Silva Junqueira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Diogo Rizzato Lara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jaderson Costa DaCosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cristina Maria Moriguchi Jeckel
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Régis Gemerasca Mestriner
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Léder Leal Xavier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pedro Porto Alegre Baptista.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baptista, P.P.A., Saur, L., Bagatini, P.B. et al. Antidepressant Effects of Ketamine Are Not Related to 18F-FDG Metabolism or Tyrosine Hydroxylase Immunoreactivity in the Ventral Tegmental Area of Wistar Rats. Neurochem Res 40, 1153–1164 (2015). https://doi.org/10.1007/s11064-015-1576-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1576-3

Keywords

Search

Navigation