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Differential levels of brain amino acids in rat models presenting learned helplessness or non-learned helplessness

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Abstract

Rationale

Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model).

Objectives

We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression.

Methods

LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography.

Results

The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals.

Conclusions

The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression.

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References

  • Anderson KJ, Maley BE, Scheff SW (1986) Immunocytochemical localization of gamma-aminobutyric acid in the rat hippocampal formation. Neurosci Lett 69:7–12

    Article  PubMed  CAS  Google Scholar 

  • Aoyama C, Santa T, Tsunoda M, Fukushima T, Kitada C, Imai K (2004) A fully automated amino acid analyzer using NBD-F as a fluorescent derivatization reagent. Biomed Chromatogr 18:630–636

    Article  PubMed  CAS  Google Scholar 

  • Bechtholt-Gompf AJ, Walther HV, Adams MA, Carlezon WA Jr, Ongur D, Cohen BM (2010) Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory. Neuropsychopharmacology 35:2049–2059

    Article  PubMed  CAS  Google Scholar 

  • Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, Matthews PM, Cowen PJ (2008) Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol 11:255–260

    Article  PubMed  CAS  Google Scholar 

  • Bowdler JM, Green AR, Minchin MC, Nutt DJ (1983) Regional GABA concentration and [3H]-diazepam binding in rat brain following repeated electroconvulsive shock. J Neural Transm 56:3–12

    Article  PubMed  CAS  Google Scholar 

  • Chapman AG, Riley K, Evans MC, Meldrum BS (1982) Acute effects of sodium valproate and gamma-vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-[14C]glucose into amino acids. Neurochem Res 7:1089–1105

    Article  PubMed  CAS  Google Scholar 

  • Christensen T, Bisgaard CF, Wiborg O (2011) Biomarkers of anhedonic-like behavior, antidepressant drug refraction, and stress resilience in a rat model of depression. Neuroscience 196:66–79

    Article  PubMed  CAS  Google Scholar 

  • Christianson JP, Thompson BM, Watkins LR, Maier SF (2009) Medial prefrontal cortical activation modulates the impact of controllable and uncontrollable stressor exposure on a social exploration test of anxiety in the rat. Stress 12:445–450

    Article  PubMed  Google Scholar 

  • Delgado y Palacios R, Campo A, Henningsen K, Verhoye M, Poot D, Dijkstra J, Van Audekerke J, Benveniste H, Sijbers J, Wiborg O, Van der Linden A (2011) Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model. Biol Psychiatry 70:449–457

    Article  PubMed  Google Scholar 

  • Edwards E, Johnson J, Anderson D, Turano P, Henn FA (1986) Neurochemical and behavioral consequences of mild, uncontrollable shock: effects of PCPA. Pharmacol Biochem Behav 25:415–421

    Article  PubMed  CAS  Google Scholar 

  • Gabbay V, Mao X, Klein RG, Ely BA, Babb JS, Panzer AM, Alonso CM, Shungu DC (2012) Anterior cingulate cortex gamma-aminobutyric acid in depressed adolescents: relationship to anhedonia. Arch Gen Psychiatry 69:139–149

    Article  PubMed  CAS  Google Scholar 

  • Grahn RE, Watkins LR, Maier SF (2000) Impaired escape performance and enhanced conditioned fear in rats following exposure to an uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus. Behav Brain Res 112:33–41

    Article  PubMed  CAS  Google Scholar 

  • Greenberg L, Edwards E, Henn FA (1989) Dexamethasone suppression test in helpless rats. Biol Psychiatry 26:530–532

    Article  PubMed  CAS  Google Scholar 

  • Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64:193–200

    Article  PubMed  CAS  Google Scholar 

  • Holm MM, Nieto-Gonzalez JL, Vardya I, Henningsen K, Jayatissa MN, Wiborg O, Jensen K (2011) Hippocampal GABAergic dysfunction in a rat chronic mild stress model of depression. Hippocampus 21:422–433

    Article  PubMed  CAS  Google Scholar 

  • Horio M, Kohno M, Fujita Y, Ishima T, Inoue R, Mori H, Hashimoto K (2011) Levels of D-serine in the brain and peripheral organs of serine racemase (Srr) knock-out mice. Neurochem Int 59:853–859

    Article  PubMed  CAS  Google Scholar 

  • Huang YH, Cheng CY, Hong CJ, Tsai SJ (2004) Expression of c-Fos-like immunoreactivity in the brain of mice with learned helplessness. Neurosci Lett 363:280–283

    Article  PubMed  CAS  Google Scholar 

  • Iwata M, Shirayama Y, Ishida H, Hazama GI, Nakagome K (2011) Hippocampal astrocytes are necessary for antidepressant treatment of learned helplessness rats. Hippocampus 21:877–884

    PubMed  CAS  Google Scholar 

  • Kanamori K, Ross BD, Kondrat RW (2002) Glial uptake of neurotransmitter glutamate from the extracellular fluid studied in vivo by microdialysis and (13)C NMR. J Neurochem 83:682–695

    Article  PubMed  CAS  Google Scholar 

  • Karolewicz B, Maciag D, O’Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G (2010) Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 13:411–420

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi H, Iwata M, Mitani H, Yamada T, Nakagome K, Kaneko K (2012) Valproic acid improves the tolerance for the stress in learned helplessness rats. Neurosci Res 72:355–363

    Article  PubMed  CAS  Google Scholar 

  • Kohen R, Kirov S, Navaja GP, Happe HK, Hamblin MW, Snoddy JR, Neumaier JF, Petty F (2005) Gene expression profiling in the hippocampus of learned helpless and nonhelpless rats. Pharmacogenomics J 5:278–291

    Article  PubMed  CAS  Google Scholar 

  • Korf J, Venema K (1983) Desmethylimipramine enhances the release of endogenous GABA and other neurotransmitter amino acids from the rat thalamus. J Neurochem 40:946–950

    Article  PubMed  CAS  Google Scholar 

  • Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, Henn F, Malinow R (2011) Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470:535–539

    Article  PubMed  CAS  Google Scholar 

  • Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, Morrison JH, McEwen BS (2006) Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 26:7870–7874

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Verkerk R, Vandoolaeghe E, Lin A, Scharpe S (1998) Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity. Acta Psychiatr Scand 97:302–308

    Article  PubMed  CAS  Google Scholar 

  • Mallei A, Giambelli R, Gass P, Racagni G, Mathe AA, Vollmayr B, Popoli M (2011) Synaptoproteomics of learned helpless rats involve energy metabolism and cellular remodeling pathways in depressive-like behavior and antidepressant response. Neuropharmacology 60:1243–1253

    Article  PubMed  CAS  Google Scholar 

  • Möhler H (2012) The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 62:42–53

    Article  PubMed  Google Scholar 

  • Nankai M, Yamada S, Muneoka K, Toru M (1995) Increased 5-HT2 receptor-mediated behavior 11 days after shock in learned helplessness rats. Eur J Pharmacol 281:123–130

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell T, Rotzinger S, Ulrich M, Hanstock CC, Nakashima TT, Silverstone PH (2003) Effects of chronic lithium and sodium valproate on concentrations of brain amino acids. Eur Neuropsychopharmacol 13:220–227

    Article  PubMed  Google Scholar 

  • Olive MF, Mehmert KK, Hodge CW (2000) Microdialysis in the mouse nucleus accumbens: a method for detection of monoamine and amino acid neurotransmitters with simultaneous assessment of locomotor activity. Brain Res Brain Res Protocol 5:16–24

    Article  CAS  Google Scholar 

  • Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95:13290–13295

    Article  PubMed  CAS  Google Scholar 

  • Petty F, Kramer GL, Gullion CM, Rush AJ (1992) Low plasma gamma-aminobutyric acid levels in male patients with depression. Biol Psychiatry 32:354–363

    Article  PubMed  CAS  Google Scholar 

  • Price RB, Shungu DC, Mao X, Nestadt P, Kelly C, Collins KA, Murrough JW, Charney DS, Mathew SJ (2009) Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol Psychiatry 65:792–800

    Article  PubMed  CAS  Google Scholar 

  • Rajkowska G, O'Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ (2007) GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 32:471–482

    Article  PubMed  CAS  Google Scholar 

  • Sakurai S, Ishii S, Umino A, Shimazu D, Yamamoto N, Nishikawa T (2004) Effects of psychotomimetic and antipsychotic agents on neocortical and striatal concentrations of various amino acids in the rat. J Neurochem 90:1378–1388

    Article  PubMed  CAS  Google Scholar 

  • Salvadore G, van der Veen JW, Zhang Y, Marenco S, Machado-Vieira R, Baumann J, Ibrahim LA, Luckenbaugh DA, Shen J, Drevets WC, Zarate CA (2011) An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression. Int J Neuropsychopharmacol 1–10

  • Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159:663–665

    Article  PubMed  Google Scholar 

  • Sanacora G, Mason GF, Rothman DL, Hyder F, Ciarcia JJ, Ostroff RB, Berman RM, Krystal JH (2003) Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 160:577–579

    Article  PubMed  Google Scholar 

  • Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF (2004) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705–713

    Article  PubMed  CAS  Google Scholar 

  • Sartorius A, Mahlstedt MM, Vollmayr B, Henn FA, Ende G (2007) Elevated spectroscopic glutamate/gamma-amino butyric acid in rats bred for learned helplessness. Neuroreport 18:1469–1473

    Article  PubMed  CAS  Google Scholar 

  • Sherman AD, Sacquitne JL, Petty F (1982) Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16:449–454

    Article  PubMed  CAS  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 

  • Shirayama Y, Muneoka K, Fukumoto M, Tadokoro S, Fukami G, Hashimoto K, Iyo M (2011) Infusions of allopregnanolone into the hippocampus and amygdala, but not into the nucleus accumbens and medial prefrontal cortex, produce antidepressant effects on the learned helplessness rats. Hippocampus 21:1105–1113

    Article  PubMed  CAS  Google Scholar 

  • Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG (1998) Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci U S A 95:316–321

    Article  PubMed  CAS  Google Scholar 

  • Sibson NR, Mason GF, Shen J, Cline GW, Herskovits AZ, Wall JE, Behar KL, Rothman DL, Shulman RG (2001) In vivo (13)C NMR measurement of neurotransmitter glutamate cycling, anaplerosis and TCA cycle flux in rat brain during. J Neurochem 76:975–989

    Article  PubMed  CAS  Google Scholar 

  • Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R (1996) Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29:23–26

    Article  PubMed  CAS  Google Scholar 

  • Smalheiser NR, Lugli G, Rizavi HS, Zhang H, Torvik VI, Pandey GN, Davis JM, Dwivedi Y (2011) MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness. Int J Neuropsychopharmacol: 1–11

  • Takahashi YK, Roesch MR, Stalnaker TA, Haney RZ, Calu DJ, Taylor AR, Burke KA, Schoenbaum G (2009) The orbitofrontal cortex and ventral tegmental area are necessary for learning from unexpected outcomes. Neuron 62:269–280

    Article  PubMed  CAS  Google Scholar 

  • Taneja M, Salim S, Saha K, Happe HK, Qutna N, Petty F, Bylund DB, Eikenburg DC (2011) Differential effects of inescapable stress on locus coeruleus GRK3, alpha(2)-adrenoceptor and CRF(1) receptor levels in learned helpless and non-helpless rats: A potential link to stress resilience. Behav Brain Res 221:25–33

    Article  PubMed  CAS  Google Scholar 

  • Videbech P (2000) PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand 101:11–20

    Article  PubMed  CAS  Google Scholar 

  • Walter M, Henning A, Grimm S, Schulte RF, Beck J, Dydak U, Schnepf B, Boeker H, Boesiger P, Northoff G (2009) The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch Gen Psychiatry 66:478–486

    Article  PubMed  CAS  Google Scholar 

  • Willner P (1986) Validation criteria for animal models of human mental disorders: learned helplessness as a paradigm case. Prog Neuropsychopharmacol Biol Psychiatry 10:677–690

    Article  PubMed  CAS  Google Scholar 

  • Xu S, Yang J, Li CQ, Zhu W, Shen J (2005) Metabolic alterations in focally activated primary somatosensory cortex of alpha-chloralose-anesthetized rats measured by 1H MRS at 11.7 T. NeuroImage 28:401–409

    Article  PubMed  Google Scholar 

  • Yang J, Shen J (2005) In vivo evidence for reduced cortical glutamate-glutamine cycling in rats treated with the antidepressant/antipanic drug phenelzine. Neuroscience 135:927–937

    Article  PubMed  CAS  Google Scholar 

  • Yuksel C, Ongur D (2010) Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 68:785–794

    Article  PubMed  Google Scholar 

  • Zazpe A, Artaiz I, Labeaga L, Lucero ML, Orjales A (2007) Reversal of learned helplessness by selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability. Neuropharmacology 52:975–984

    Article  PubMed  CAS  Google Scholar 

  • Zink M, Vollmayr B, Gebicke-Haerter PJ, Henn FA (2010) Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology 58:465–473

    Article  PubMed  CAS  Google Scholar 

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The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan

    Katsumasa Muneoka & Masaomi Iyo

  2. Department of Anatomy I, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, 142-8555, Japan

    Katsumasa Muneoka

  3. Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, 290-0111, Japan

    Yukihiko Shirayama

  4. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan

    Yukihiko Shirayama, Mao Horio & Kenji Hashimoto

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  1. Katsumasa Muneoka
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  2. Yukihiko Shirayama
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  3. Mao Horio
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  4. Masaomi Iyo
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  5. Kenji Hashimoto
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Correspondence to Katsumasa Muneoka.

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Muneoka, K., Shirayama, Y., Horio, M. et al. Differential levels of brain amino acids in rat models presenting learned helplessness or non-learned helplessness. Psychopharmacology 229, 63–71 (2013). https://doi.org/10.1007/s00213-013-3080-2

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  • DOI: https://doi.org/10.1007/s00213-013-3080-2

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