SpringerLink
Log in

Glutamate and modeling of schizophrenia symptoms: Review of our Findings: 1990–2014

  • Review article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

In the early 90s, we studied the role of perception disturbances in schizophrenia in our first clinical approaches, using the Bender test in schizophrenic patients. Results were clear, showing a shape discrimination failure. Following this initial results, we reproduced nuclear symptoms of schizophrenia in animal models, showing that perceptual disturbances, acquisition disturbances, decrease in affective levels and working memory disturbances can be induced by specific N-methyl-d-aspartic acid (NMDA) glutamatergic blockade within the nucleus accumbens septi (NAS). We studied also another glutamatergic and dopaminergic drugs, finding that a decrease in glutamatergic transmission within NAS led to cognitive disturbances and affective flattening. An increase in glutamatergic transmission fully enhances cognition in the tasks used. Dopaminergic D-2 antagonists partially improved cognition. Our results link the proposed corticostriatal dysfunction with the thalamocortical disturbances underlying perceptual problems, but also influencing affective levels and cognitive variables. According to our translational findings, core schizophrenia symptoms may be translationally reproduced antagonizing NMDA receptors within NAS, and improved blocking the glutamate auto-receptor. Dopaminergic transmission appears to have a role in therapeutic but not in the early pathophysiology of schizophrenia.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Amitai N, Markou A. Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia. Biol Psychiatry 2010;68:5–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Matthysse S. Making animal models relevant to psychiatry. Ann NY Acad Sci 1983;406:133–9.

    Article  CAS  PubMed  Google Scholar 

  3. McKinney Jr WT. Animal models in psychiatry. Perspect Biol Med 1974;17:529–42.

    Article  PubMed  Google Scholar 

  4. McKinney WT, Moran EC. Animal models of schizophrenia. Am J Psychiatry 1981;138:478–83.

    Article  CAS  PubMed  Google Scholar 

  5. Kaffman A, Krystal JH. New frontiers in animal research of psychiatric illness. Methods Mol Biol 2012;829:3–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Machado-Vieira R. Tracking the impact of translational research in psychiatry: state of the art and perspectives. J Transl Med 2012;10:175.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gargiulo PA, Viana MB, Graeff FG, Silva MA, Tomaz C. Effects of anxiety and memory of systemic and intra-amygdala injection of 5-HT3 receptor antagonist BRL 46470A. Neuropsychobiology 1996;33:189–95.

    Article  CAS  PubMed  Google Scholar 

  8. Gargiulo PA, Donoso AO. Distinct grooming patterns induced by intracerebroventricular injection of CRH, TRH and LHRH in male rats. Braz J Med Biol Res 1996;29:375–9.

    CAS  PubMed  Google Scholar 

  9. Grace AA. Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Rev 2000;31:330–41; Graeff FG, Zangrossi Jr H. The dual role of serotonin in defense and the mode of action of antidepressants on generalized anxiety and panic disorders. Cent Nerv Syst Agents Med Chem 2010;10:207–17.

    Article  CAS  PubMed  Google Scholar 

  10. Haller J, Alicki M. Current animal models of anxiety, anxiety disorders, and anxiolytic drugs. Curr Opin Psychiatry 2012;25:59–64.

    Article  PubMed  Google Scholar 

  11. Camplesi Jr M, de Bortoli VC, de Paula Soares V, Nogueira RL, Zangrossi Jr H. Dorsal periaqueductal gray stimulation facilitates anxiety-, but not panic-related, defensive responses in rats tested in the elevated T-maze. Braz J Med Biol Res 2012;45:1025–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Roncon CM, Biesdorf C, Santana RG, Zangrossi Jr H, Graeff FG, Audi EA. The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey. J Psychopharmacol 2012;26:525–31.

    Article  CAS  PubMed  Google Scholar 

  13. Berton O, Hahn CG, Thase ME. Are we getting closer to valid translational models for major depression? Science 2012;338:75–9.

    Article  CAS  PubMed  Google Scholar 

  14. Dzirasa K, Covington III HE. Increasing the validity of experimental models for depression. Ann NY Acad Sci 2012;1265:36–45.

    Article  PubMed  Google Scholar 

  15. Young JW, Henry BL, Geyer MA. Predictive animal models of mania: hits, misses and future directions. Br J Pharmacol 2011;164:1263–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Geyer MA. Develo** translational animal models for symptoms of schizophrenia or bipolar mania. Neurotox Res 2008;14:71–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Baune BT, Thome J. Translational research approach to biological and modifiable risk factors of psychosis and affective disorders. World J Biol Psychiatry 2011;12(Suppl. 1):28–34.

    Article  PubMed  Google Scholar 

  18. Halberstadt AL, Geyer MA. Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 2011;61:364–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hanks JB, González-Maeso J. Animal models of serotonergic psychedelics. ACS Chem Neurosci 2013;4:33–42.

    Article  CAS  PubMed  Google Scholar 

  20. Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharmacol 2011;164:1162–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gargiulo PA. Popper and psychopathology: some possible implications of his thought. In: Gargiulo PA, editor. On hopelessness and other psychological studies. Germany: Editorial Académica Espańola, AV Akademiker Verlag Gmbh & Co. K.G. Saarbrücken; 2012 (Spanish).

    Google Scholar 

  22. Huber G. The psychopathology of K. Jaspers and K. Schneider as a fundamental method for psychiatry. World J Biol Psychiatry 2002;3:50–7.

    Article  PubMed  Google Scholar 

  23. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, ‘‘just the facts’’ 5. Treatment and prevention. Past, present, and future. Schizophr Res 2010;122:1–23.

    Article  PubMed  Google Scholar 

  24. Feldon J, Weiner I. From an animal model of an attentional deficit towards new insights into the pathophysiology of schizophrenia. J Psychiatr Res 1992;26:345–66.

    Article  CAS  PubMed  Google Scholar 

  25. Grace AA. Cortical regulation of subcortical dopamine systems and its possible relevance to schizophrenia. J Neural Transm Gen Sect 1993;91:111–34.

    Article  CAS  PubMed  Google Scholar 

  26. Gray JA. Integrating schizophrenia. Schizophr Bull 1998;24:249–66.

    Article  CAS  PubMed  Google Scholar 

  27. Matthysse S. Schizophrenia: relationship to dopamine transmission, motor control and feature extraction. In: The neurosciences: third study program. Cambridge, MA: MIT Press; 1974. p. 733–7.

    Google Scholar 

  28. Matthysse S. Nucleus accumbens and schizophrenia. In: Chronister RB, De France JF, editors. The neurobiology of the nucleus accumbens, Sebasco Estaes. 1980. p. 351–9. Haer Institute. Proceedings of the symposium: nucleus acumbens, Sebasco Estaes, Maine, 1980.

    Google Scholar 

  29. O’Donnell P, Grace AA. Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophr Bull 1998;24:267–83.

    Article  PubMed  Google Scholar 

  30. Matthysse S. Antipsychotic drug actions: a clue to neuropathology of schizophrenia? Fed Proc 1973;32:200–5.

    CAS  PubMed  Google Scholar 

  31. Schneider K. Clinical psychopathology.(Hamilton M.W., Trans.) New York: Grune and Stratton; 1959.

    Google Scholar 

  32. Crow TJ. Molecular pathology of schizophrenia: more than one disease process? Br Med J 1980;280:66–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Crow TJ. The two-syndrome concept: origins and current status. Schizophr Bull 1985;11:471–86.

    Article  CAS  PubMed  Google Scholar 

  34. Reichenberg A, Harvey PD, Bowie CR, Mojtabai R, Rabinowitz J, Heaton RK, et al. Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders. Schizophr Bull 2009;35:1022–9.

    Article  PubMed  Google Scholar 

  35. Acerbo MJ, Gargiulo PA, Krug I, Delius JD. Behavioural consequences of nucleus accumbens dopaminergic stimulation and glutamatergic blocking in pigeons. Behav Brain Res 2002;136:171–7.

    Article  CAS  PubMed  Google Scholar 

  36. Conrad K. Die beginnende Schizophrenie. Versuch einer Gestaltanalyse des Wahnsinns. Incipient schizophrenia: an attempt at a gestaltic analysis of insanity Stuttgart: Thieme; 1966.

    Google Scholar 

  37. Costello CG. Symptoms of schizophrenia. New York, NY: Wiley; 1993.

    Google Scholar 

  38. Gargiulo PA, Siemann M, Delius JD. Visual discrimination in pigeons impaired by glutamatergic blockade of nucleus accumbens. Physiol Behav 1998;63: 705–9.

    Article  CAS  PubMed  Google Scholar 

  39. Gargiulo PA, Acerbo MJ, Krug I, Delius JD. Cognitive effects of dopaminergic and glutamatergic blockade in nucleus accumbens in pigeons. Pharmacol Biochem Behav 2005;81:732–9.

    Article  CAS  PubMed  Google Scholar 

  40. Martínez G, Ropero C, Funes A, Flores E, Blotta C, Landa AI, et al. Effects of NMDA and non-NMDA blockade in the nucleus accumbens on the plus maze test. Physiol Behav 2002;76:219–24.

    Article  PubMed  Google Scholar 

  41. Martínez G, Ropero C, Funes A, Flores E, Landa AI, Gargiulo PA. AP-7 into the nucleus accumbens disrupts acquisition but does not affect consolidation in a passive avoidance task. Physiol Behav 2002;76:205–12.

    Article  PubMed  Google Scholar 

  42. Baiardi G, Ruiz AM, Beling A, Borgonovo J, Martinez G, Landa AI, et al. Glutamatergic ionotropic blockade within accumbens disrupts working memory and might alter the endocytic machinery in rat accumbens and prefrontal cortex. J Neural Transm 2007;114:1519–28.

    Article  CAS  PubMed  Google Scholar 

  43. Gargiulo PA, Landa de Gargiulo AI. Perception and psychoses: the role of glutamatergic transmission within tne nucleus Accumbens Septi. Behav Brain Sci 2004;27:792–3.

    Article  Google Scholar 

  44. Del Vecchio S, Gargiulo PA. Visual and motor function in schizophrenic patients. Acta Psiquiatr Psicol Am Lat 1992;38:317–22.

    PubMed  Google Scholar 

  45. Gargiulo PA, Del Vecchio S. Gestaltic visual motor function in schizophrenic patients. Göttingen Neurobiology Report 1997. In: Elsner N, Wässle H, editors. Proceedings of the 25th Göttingen neurobiology conference 1997, Vol. II, Communication 1005. Stuttgart: Thieme; 1997.

    Google Scholar 

  46. Gargiulo PA. Aproximaciones Experimentales a la Percepción Delirante Experimental approaches to delusional perception Alcmeón Rev Argent Neuropsiquiatr 2001;37:18–30.

    Google Scholar 

  47. Gargiulo PA. Aproximaciones Experimentales al a Disfunción perceptual en la Esquizofrenia Experimental approaches to perceptual dysfunction in schizophrenia Rev Neurol (Spain) 2003;6:545–51.

    Google Scholar 

  48. Holden C. Deconstructing schizophrenia. Science 2003;299:333–5.

    Article  CAS  PubMed  Google Scholar 

  49. Yoon JH, Sheremata SL, Rokem A, Silver MA. Windows to the soul: vision science as a tool for studying biological mechanisms of information processing deficits in schizophrenia. Front Psychol 2013;4:681.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Matussek P. Untersuchungen über die Wahnwahrnehmungen Studies on the delusional perceptions, German Arch Psychiatr Nervenkr 1952;189:279–318.

    Article  CAS  Google Scholar 

  51. Kleinman JE, Gillin JC, Wyatt RJ. A comparison of the phenomenology of hallucinogens and schizophrenia from some autobiographical accounts. Schizophr Bull 1977;3:560–86.

    Article  CAS  PubMed  Google Scholar 

  52. Green MF, Nuechterlein KH, Breitmeyer B, Mintz J. Backward masking in unmedicated schizophrenic patients in psychotic remission: possible reflection of aberrant cortical oscillation. Am J Psychiat 1999;156:1367–73.

    CAS  PubMed  Google Scholar 

  53. Delius JD, Hollard VD. Orientation invariant pattern recognition by pigeons (Columba livia) and humans (Homo sapiens). J Comp Psychol 1995;109:278–90.

    Article  CAS  PubMed  Google Scholar 

  54. Aleman A, Kahn RS. Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Prog Neurobiol 2005;77:283–98.

    PubMed  Google Scholar 

  55. Llano Lopez L, Caif F, Fraile M, Tinnirello B, Landa A, Lafuente JV, et al. Differential behavioral profile induced by the injection of dipotassium chlorazepate within brain areas that project to the nucleus accumbens septi. Pharmacol Rep 2013;65:566–78.

    Article  PubMed  Google Scholar 

  56. Gargiulo PA, Martinez G, Ropero C, Funes A, Landa AI. NMDA glutamatergic blockade of nucleus accumbens disrupts acquisition but not consolidation in a passive avoidance task. Ann NY Acad Sci 1999;877:717–22.

    Article  CAS  PubMed  Google Scholar 

  57. Carlsson A, Waters N, Waters S, Carlsson ML. Network interactions in schizophrenia-therapeutic implications. Brain Res Brain Res Rev 2000;31: 342–9.

    Article  CAS  PubMed  Google Scholar 

  58. Kelley AE, Andrzejewski ME, Baldwin AE, Hernandez PJ, Pratt WE. Glutamate-mediated plasticity in corticostriatal networks. Role in adaptive motor learning. Ann NY Acad Sci 2003;1003:159–68.

    Article  CAS  PubMed  Google Scholar 

  59. Sesack SR, Pickel VM. In the rat medial nucleus accumbens, hippocampal and catecholaminergic terminals converge on spiny neurons and are in apposition to each other. Brain Res 1990;527:266–79.

    Article  CAS  PubMed  Google Scholar 

  60. Mogenson GJ, Yang CR, Yim CY. Influence of dopamine on limbic inputs to the nucleus accumbens. Ann NY Acad Sci 1988;537:86–100.

    Article  CAS  PubMed  Google Scholar 

  61. O’Donnell P, Grace AA. Tonic D2-mediated attenuation of cortical excitation in nucleus accumbens neurons recorded in vitro. Brain Res 1994;634: 105–12.

    Article  PubMed  Google Scholar 

  62. O’Donnell P, Grace AA. Dopaminergic reduction of excitability in nucleus accumbens neurons recorded in vitro. Neuropsychopharmacology 1996;15: 87–97.

    Article  PubMed  Google Scholar 

  63. Pennartz CMA, Dollerman-van der Weel MJ, Kitai ST, Lopes da Silva FH. Presynaptic dopamine D1 receptors attenuate excitatory and inhibitory limbic inputs to the shell region of the rat nucleus accumbens. J Neurophysiol 1992;1325–34.

    Google Scholar 

  64. Yim CY, Mogenson GJ. Mesolimbic dopamine projection modulates amygdala-evoked EPSP in nucleus accumbens neurons: an in vivo study. Brain Res 1986;369:347–52.

    Article  CAS  PubMed  Google Scholar 

  65. Richfield EK, Penney JB, Young AB. Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system. Neuroscience 1989;30:767–77.

    Article  CAS  PubMed  Google Scholar 

  66. Grace AA. The depolarization block hypothesis of neuroleptic action: implications for the etiology and treatment of schizophrenia. J Neural Transm Suppl 1992;36:91–131.

    CAS  PubMed  Google Scholar 

  67. Valenti O, Grace AA. Antipsychotic drug-induced increases in ventral tegmental area dopamine neuron population activity via activation of the nucleus accumbens-ventral pallidum pathway. Int J Neuropsychopharmacol 2010;13:845–60.

    Article  CAS  PubMed  Google Scholar 

  68. Grace AA, Bunney BS, Moore H, Todd CL. Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci 1997;20:31–7.

    Article  CAS  PubMed  Google Scholar 

  69. Valenti O, Cifelli P, Gill KM, Grace AA. Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia. J Neurosci 2011;31:12330–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Holden C. Excited by glutamate. Science 2003;300:1866–8.

    Article  CAS  PubMed  Google Scholar 

  71. Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 2012;37:4–15.

    Article  CAS  PubMed  Google Scholar 

  72. Noetzel MJ, Jones CK, Conn PJ. Emerging approaches for treatment of schizophrenia: modulation of glutamatergic signaling. Discov Med 2012;14:335–43.

    PubMed  PubMed Central  Google Scholar 

  73. Onitsuka T, Oribe N, Nakamura I, Kanba S. Review of neurophysiological findings in patients with schizophrenia. Psychiatry Clin Neurosci 2013;67: 461–70.

    Article  PubMed  Google Scholar 

  74. Palmer BW, Dawes SE, Heaton RK. What do we know about neuropsychological aspects of schizophrenia? Neuropsychol Rev 2009;19:365–84.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Rao NP. Pathogenetic and therapeutic perspectives on neurocognitive models in psychiatry: a synthesis of behavioral, brain imaging, and biological studies. Indian J Psychiatry 2012;54:217–22.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Darke H, Peterman JS, Park S, Sundram S, Carter O. Are patients with schizophrenia impaired in processing non-emotional features of human faces? Front Psychol 2013;4:529.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Giersch A, Lalanne L, van Assche M, Elliott MA. On disturbed time continuity in schizophrenia: an elementary impairment in visual perception? Front Psychol 2013;4:281.

    PubMed  PubMed Central  Google Scholar 

  78. Volman SF, Lammel S, Margolis EB, Kim Y, Richard JM, Roitman MF, et al. New insights into the specificity and plasticity of reward and aversion encoding in the mesolimbic system. J Neurosci 2013;33:17569–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Carlsson M, Carlsson A. The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 1989;75:221–6.

    Article  CAS  PubMed  Google Scholar 

  80. Kantrowitz JT, Javitt DC. Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models. Clin Schizophr Relat Psychoses 2010;4:189–200.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Snyder MA, Gao WJ. NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front Cell Neurosci 2013;7:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rao VS, Carvalho AC, Trevisan MT, Andrade GM, Nobre-Júnior HV, Moraes MO, et al. Mangiferin ameliorates 6-hydroxydopamine-induced cytotoxicity and oxidative stress in ketamine model of schizophrenia. Pharmacol Rep 2012;64:848–56.

    Article  CAS  PubMed  Google Scholar 

  83. Rogóż Z. Effect of co-treatment with mirtazapine and risperidone in animal models of the positive symptoms of schizophrenia in mice. Pharmacol Rep 2012;64:1567–72.

    Article  PubMed  Google Scholar 

  84. Wędzony K, Fijał K, Maćkowiak M, Chocyk A. Detrimental effect of postnatal blockade of N-methyl-D-aspartate receptors on sensorimotor gating is reversed by neuroleptic drugs. Pharmacol Rep 2008;60:856–64.

    PubMed  Google Scholar 

  85. Wędzony K, Markowicz-Kula K, Chocyk A, Fijał K, Przyborowska A, Maćkowiak M. Impact of postnatal dexamethasone on psychotomimetic effects of MK-801 measured on adult rats. Pharmacol Rep 2009;61:1034–41.

    Article  PubMed  Google Scholar 

  86. Keshavan MS, Kaneko Y. Secondary psychoses: an update. World Psychiatry 2013;12:4–15.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Rompala GR, Zsiros V, Zhang S, Kolata SM, Nakazawa K. Contribution of NMDA receptor hypofunction in prefrontal and cortical excitatory neurons to schizophrenia-like phenotypes. PLoS ONE 2013;8(4):e61278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sacchetti E, Scassellati C, Minelli A, Valsecchi P, Bonvicini C, Pasqualetti P, et al. Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes. BMC Med Genet 2013;14:33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Timms AE, Dorschner MO, Wechsler J, Choi KY, Kirkwood R, Girirajan S, et al. Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families. JAMA Psychiatry 2013;70:582–90.

    Article  CAS  PubMed  Google Scholar 

  90. Schwartz TL, Sachdeva S, Stahl SM. Genetic data supporting the NMDA glutamate receptor hypothesis for schizophrenia. Curr Pharm Des 2012;18: 1580–92.

    Article  CAS  PubMed  Google Scholar 

  91. Javitt DC. Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol 2012;213:367–99.

    Article  CAS  Google Scholar 

  92. Javitt DC, Zukin SR, Heresco-Levy U, Umbricht D. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull 2012;38:958–66.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 1998;281:1349–52.

    Article  CAS  PubMed  Google Scholar 

  94. File SE. Sedative effects of PK 9084 and PK 8165, alone and in combination with chlordiazepoxide. Br J Pharmacol 1983;79:219–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schwartz TL, Sachdeva S, Stahl SM. Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Front Pharmacol 2012;3:195.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007;13:1102–7.

    Article  CAS  PubMed  Google Scholar 

  97. Sumiyoshi T, Higuchi Y, Uehara T. Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia. Front Behav Neurosci 2013;7:140.

    PubMed  PubMed Central  Google Scholar 

  98. Khorana AB, Patel Y. Comparative short-term evaluation of penfluridol and trifluoperazine in chronic schizophrenia. Indian J Physiol Pharmacol 1988;32:293–8.

    CAS  PubMed  Google Scholar 

  99. Marques LO, Lima MS, Soares BG. Trifluoperazine for schizophrenia. Cochrane Database Syst Rev 2004;CD003545.

    Google Scholar 

  100. Donnelly L, Rathbone J, Adams CE. Haloperidol dose for the acute phase of schizophrenia. Cochrane Database Syst Rev 2013;8:CD001951.

    Google Scholar 

  101. Marder SR. Limitations of dopamine-D2 antagonists and the search for novel antipsychotic strategies. Neuropharmacology 1999;21:S117–21.

    CAS  Google Scholar 

  102. Meltzer HY, Arvanitis L, Bauer D, Rein W, Meta-Trial Study Group. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 2004;161: 975–84.

    Article  PubMed  Google Scholar 

  103. Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, et al. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 2011;31:349–55.

    Article  CAS  PubMed  Google Scholar 

  104. Moghaddam B, Krystal JH. Capturing the angel in ‘‘angel dust’’: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull 2012;38:942–9.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 2013;73:1133– 41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR. Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo. Eur Neuropsychopharmacol 2012;22:308–17.

    Article  CAS  PubMed  Google Scholar 

  107. Poels EM, Kegeles LS, Kantrowitz JT, Slifstein M, Javitt DC, Lieberman JA, et al. Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. Mol Psychiatry 2013. http://dx.doi.org/10.1038/mp.2013.136.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Neurosciences and Experimental Psychology, Institute of Experimental Medicine and Biology of Cuyo (IMBECU), Argentine National Council of Scientific and Technological Research (CONICET), Mendoza, Argentina

    Pascual Ángel Gargiulo & Adriana Inés Landa De Gargiulo

  2. Area of Pharmacology, Department of Pathology, Faculty of Medical Sciences, National University of Cuyo, Ciudad Universitaria, Parque General San Martın, Mendoza, Argentina

    Pascual Ángel Gargiulo & Adriana Inés Landa De Gargiulo

  3. Latin American Technological Corporation Foundation (FUCOTEL), Mendoza, Argentina

    Pascual Ángel Gargiulo & Adriana Inés Landa De Gargiulo

Authors
  1. Pascual Ángel Gargiulo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adriana Inés Landa De Gargiulo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pascual Ángel Gargiulo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gargiulo, P.Á., De Gargiulo, A.I.L. Glutamate and modeling of schizophrenia symptoms: Review of our Findings: 1990–2014. Pharmacol. Rep 66, 343–352 (2014). https://doi.org/10.1016/j.pharep.2014.03.010

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2014.03.010

Keywords

Search

Navigation