Neurotoxicity Research

, Volume 14, Issue 2–3, pp 97–104 | Cite as

Hippocampal dysfunction and disruption of dopamine system regulation in an animal model of schizophrenia

  • Daniel J. Lodge
  • Anthony A. Grace


Studies into the pathophysiology of schizophrenia have consistently demonstrated a dysfunction of dopamine (DA) system regulation in this disorder. This includes hyper-responsivity to DA agonists, the therapeutic efficacy of DA antagonists, and augmented striatal DA release in response to amphetamine. Nonetheless, there is little evidence for a pathological alteration with the DA system itself in schizophrenia. Instead, it is suggested that the disturbance lies in the manner by which the DA system is regulated. Recently, rodent models of schizophrenia have been advanced based on developmental disruption that recapitulates many of the symptoms observed in human schizophrenia patients. We found that administration of the mitotoxin methylazoxymethanol acetate (MAM) to rats at gestational day 17 leads to adult rats that exhibit neuroanatomical, pharmacological, and behavioral characteristics consistent with schizophrenia. These rats also exhibit hyperactivity within the ventral subiculum of the hippocampus that corresponds to a loss of parvalbumin-containing interneurons. This hyperactivity causes an increase in the population activity of the DA neurons(i.e., more DA neurons are firing spontaneously), thus increasing the responsivity of the DA system to stimuli. When the ventral subiculum is inactivated, DA neuron population activity is restored to baseline, and the hyperresponsivity to amphetamine is normalized to that observed in control rats. These findings demonstrate a direct link between the hippocampal pathophysiology, interneuronal alterations, and hyperdopaminergic state observed in the schizophrenia patient. Moreover, this suggests an alternate pharmacotherapeutic approach based on the normalization of hippocampal activity in the treatment of schizophrenia in humans.


Schizophrenia Dopamine Hippocampus MAM GABA Parvalbumin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abdul-Monim Z, JC Neill and GP Reynolds (2007) Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat.J. Psychopharmacol. 21(2), 198–205.PubMedCrossRefGoogle Scholar
  2. Abi-Dargham A (2004) Do we still believe in the dopamine hypothesis? New data bring new evidence.Int. J. Neuropsychopharmacol. 7 Suppl. 1, S1-S5.PubMedCrossRefGoogle Scholar
  3. Akbarian S, JJ Kim, SG Potkin, JO Hagman, A Tafazzoli, WE Bunney Jr and EG Jones (1995) Gene expression for glutamic acid decarboxylase is reduced without loss of neurons inprefrontal cortex of schizophrenics.Arch. Gen. Psychiatry 52, 258–278.PubMedGoogle Scholar
  4. Andreasen NC (1995) Symptoms, signs, and diagnosis of schizophrenia.Lancet 346(8973), 477–481.PubMedCrossRefGoogle Scholar
  5. Benes FM (2002) Is the GABA cell a final common pathway for the etiology and treatment of schizophrenia and bipolar disorder?Curr. Opin. Psychiatry 15(3), 277–278.CrossRefGoogle Scholar
  6. Benes FM and S Berretta (2001) GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder.Neuropsychopharmacol. 25(1), 1–27.CrossRefGoogle Scholar
  7. Benes FM, B Lim, D Matzilevich, JP Walsh, S Subburaju and M Minns (2007) Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars.Proc. Natl. Acad. Sci. USA 104(24), 10164–10169.PubMedCrossRefGoogle Scholar
  8. Berridge KC and TE Robinson (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?Brain Res. Rev. 28(3), 309–369.PubMedCrossRefGoogle Scholar
  9. Carlsson A, N Waters, S Waters and ML Carlsson (2000) Network interactions in schizophrenia -therapeutic implications.Brain Res. Rev. 31(2–3), 342–349.PubMedCrossRefGoogle Scholar
  10. Chergui K, H Akaoka, PJ Charlety, CF Saunier, M Buda and G Chouvet (1994) Subthalamic nucleus modulates burst firing of nigral dopamine neurones via NMDA receptors.Neuroreport 5, 1185–1188.PubMedGoogle Scholar
  11. Flagstad P, A Mork, BY Glenthoj, J van Beek, AT Michael-Titus and M Didriksen (2004) Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens.Neuropsychopharmacol. 29(11), 2052–2064.CrossRefGoogle Scholar
  12. Floresco SB, AR West, B Ash, H Moore and AA Grace (2003) Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission.Nat. Neurosci. 6(9), 968–973.PubMedCrossRefGoogle Scholar
  13. Goto Y and AA Grace (2006) Alterations in medial prefrontal cortical activity and plasticity in rats with disruption of cortical development.Biol. Psychiatry 60(11), 1259–1267.PubMedCrossRefGoogle Scholar
  14. Gourevitch R, C Rocher, G Le Pen, MO Krebs and TM Jay (2004) Working memory deficits in adult rats after prenatal disruption of neurogenesis.Behav. Pharmacol. 15(4), 287–292.PubMedCrossRefGoogle Scholar
  15. Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia.Neuroscience 41, 1–24.PubMedCrossRefGoogle Scholar
  16. Grace AA (2000) The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.Addiction 95, Suppl. 2, S119-S128.PubMedGoogle Scholar
  17. Grace AA and H Moore (1998) Regulation of information flow in the nucleus accumbens: a model for the pathophysiology of schizophrenia, In: Origins and Development of Schizophrenia: Advances in Experimental Psychopathology (Lenzenweger MF and RH Dworkin, Eds.) (American Psychological Assn:Washington DC), pp 123–157.CrossRefGoogle Scholar
  18. Grace AA, SB Floresco, Y Goto and DJ Lodge (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors.Trends Neurosci. 30(5), 220–227.PubMedCrossRefGoogle Scholar
  19. Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation.Brain 122(4), 593–624.PubMedCrossRefGoogle Scholar
  20. Harrison PJ (2004) The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications.Psychopharmacol. 174(1), 151–162.Google Scholar
  21. Harte MK, SB Powell, NR Swerdlow, MA Geyer and GP Reynolds (2007) Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats.J. Neural Transm. 114(7), 893–898.PubMedCrossRefGoogle Scholar
  22. Hashimoto T, DW Volk, SM Eggan, K Mirnics, JN Pierri, Z Sun, AR Sampson and DA Lewis (2003) Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.J. Neurosci. 23(15), 6315–6326.PubMedGoogle Scholar
  23. Heckers S (2004) The hippocampus in schizophrenia.Am. J. Psychiatry 161(11), 2138–2139.PubMedCrossRefGoogle Scholar
  24. Heckers S and C Konradi (2002) Hippocampal neurons in schizophrenia.J. Neural Transm. 109(5), 891–905.PubMedCrossRefGoogle Scholar
  25. Heckers S, SL Rauch, D Goff, CR Savage, DL Schacter, AJ Fischman and NM Alpert (1998) Impaired recruitment of the hippocampus during conscious recollection in schizophrenia.Nat. Neurosci. 1, 318–323.PubMedCrossRefGoogle Scholar
  26. Heckers S, D Stone, J Walsh, J Shick, P Koul and FM Benes (2002) Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia.Arch. Gen. Psychiatry 59(6), 521–529.PubMedCrossRefGoogle Scholar
  27. Hornig M and WI Lipkin (2001) Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models.Ment. Retard. Dev. Disabil. Res. Rev. 7(3), 200–210.PubMedCrossRefGoogle Scholar
  28. Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia.Am. J. Psychiatry 160(1), 13–23.PubMedCrossRefGoogle Scholar
  29. Krieckhaus EE, JW Donahoe and MA Morgan (1992) Paranoid schizophrenia may be caused by dopamine hyperactivity of CA1 hippocampus.Biol. Psychiatry 31, 560–570.PubMedCrossRefGoogle Scholar
  30. Lahti AC, MA Weiler, HH Holcomb, CA Tamminga, WT Carpenter and R McMahon (2006) Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia.Neuropsychopharmacol. 31(1), 221–230.Google Scholar
  31. Laruelle M and A Abi-Dargham (1999) Dopamine as the wind of psychotic fire: new evidence from brain imaging studies.J. Psychopharmacol. 13(4), 358–371.PubMedCrossRefGoogle Scholar
  32. Legault M and RA Wise (1999) Injections of N-methyl-Daspartate into the ventral hippocampus increase extracellular dopamine in the ventral tegmental area and nucleus accumbens.Synapse 31(4), 241–249.PubMedCrossRefGoogle Scholar
  33. Lewis DA and G Gonzalez-Burgos (2008) Neuroplasticity of neocortical circuits in schizophrenia.Neuropsychopharmacol. 33, 141–165.CrossRefGoogle Scholar
  34. Lewis DA and P Levitt (2002) Schizophrenia as a disorder of neurodevelopment.Annu. Rev. Neurosci. 25, 409–432.PubMedCrossRefGoogle Scholar
  35. Lewis DA, T Hashimoto and DW Volk (2005) Cortical inhibitory neurons and schizophrenia.Nat. Rev. Neurosci. 6(4), 312–324.PubMedCrossRefGoogle Scholar
  36. Lodge DJ, and AA Grace (2006) The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation.Neuropsychopharmacol. 31(7), 1356–1361.CrossRefGoogle Scholar
  37. Lodge DJ and AA Grace (2007) Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia.J. Neurosci. 27, 11424–11430.PubMedCrossRefGoogle Scholar
  38. Lodge DJ, Behrens, M., and Grace, A. A. (2007) Diminished GABAergic regulation of hippocampal activity in an animal model of schizophrenia. In Preparation.Google Scholar
  39. Marenco S and DR Weinberger (2000) The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave.Dev. Psychopathol. 12(3), 501–527.PubMedCrossRefGoogle Scholar
  40. McNeil TF (1995) Perinatal risk factors and schizophrenia: selective review and methodological concerns.Epidemiol. Rev. 17(1), 107–112.PubMedGoogle Scholar
  41. McNeil TF, E Cantor-Graae and B Ismail (2000) Obstetric complications and congenital malformation in schizophrenia.Brain Res. Rev. 31(2–3), 166–178.PubMedCrossRefGoogle Scholar
  42. Medoff DR, HH Holcomb, AC Lahti and CA Tamminga (2001) Probing the human hippocampus using rCBF: contrasts in schizophrenia.Hippocampus 11(5), 543–550.PubMedCrossRefGoogle Scholar
  43. Meyer-Lindenberg A and DR Weinberger (2006) Intermediate phenotypes and genetic mechanisms of psychiatric disorders.Nat. Rev. Neurosci. 7(10), 818–827.PubMedCrossRefGoogle Scholar
  44. Meyer-Lindenberg A, JB Poline, PD Kohn, JL Holt, MF Egan, DR Weinberger and KF Berman (2001) Evidence for abnormal cortical functional connectivity during working memory in schizophrenia.Am. J. Psychiatry 158(11), 1809–1817.PubMedCrossRefGoogle Scholar
  45. Miyamoto S, GE DFuncan, CE Marx and JA Lieberman (2004) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs.Mol. Psychiatry 10(1), 79–104.CrossRefGoogle Scholar
  46. Moore H, JD Jentsch, M Ghajarnia, MA Geyer and AA Grace (2006) A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.Biol. Psychiatry 60(3), 253–264.PubMedCrossRefGoogle Scholar
  47. Moses SN, RJ Sutherland and RJ McDonald (2002) Differential involvement of amygdala and hippocampus in responding to novel objects and contexts.Brain Res. Bull. 58(5), 517–527.PubMedCrossRefGoogle Scholar
  48. Murray RM, P Jones, E O’Callaghan, N Takei and P Sham (1992) Genes, viruses and neurodevelopmental schizophrenia.J. Psychiatr. Res. 26, 225–235.PubMedCrossRefGoogle Scholar
  49. Nelson MD, AJ Saykin, LA Flashman and HJ Riordan (1998) Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study.Arch. Gen. Psychiatry 55(5), 433–440.PubMedCrossRefGoogle Scholar
  50. Nordahl TE, N Kusubov, C Carter, S Salamat, AM Cummings, L O’Shora-Celayaet al. (1996) Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600.Neuropsychopharmacol. 15(6), 541–554.CrossRefGoogle Scholar
  51. Ounsted C and J Lindsay (1981)Epilepsy and Psychiatry (Reynolds EH and MR Trinble, Eds.) (Churchill Livingstone:Edinburgh).Google Scholar
  52. Pearce BD (2001) Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms.Mol. Psychiatry 6(6), 634–646.PubMedCrossRefGoogle Scholar
  53. Penschuck S, P Flagstad, M Didriksen, M Leist and AT Michael-Titus (2006) Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia.Eur. J. Neurosci. 23(1), 279–284.PubMedCrossRefGoogle Scholar
  54. Reynolds GP, CL Beasley and ZJ Zhang (2002) Understanding the neurotransmitter pathology of schizophrenia: Selective deficits of subtypes of cortical GABAergic neurons.J. Neural Transm. 109(5-6), 881–889.PubMedCrossRefGoogle Scholar
  55. Saykin AJ, RC Gur, RE Gur, PD Mozley, LH Mozley, SM Resnick, DB Kester and P Stafiniak (1991) Neuropsychological function in schizophrenia. Selective impairment in memory and learning.Arch. Gen. Psychiatry 48, 618–624.PubMedGoogle Scholar
  56. Schultz W (1998) Predictive reward signal of dopamine neurons.J. Neurophysiol. 80(1), 1–27.PubMedGoogle Scholar
  57. Shenton ME, CC Dickey, M Frumin and RW McCarley (2001) A review of MRI findings in schizophrenia.Schizophr. Res. 49(1-2), 1–52.PubMedCrossRefGoogle Scholar
  58. Squire LR, CEL Stark and RE Clark (2004) The medial temporal lobe.Annu. Rev. Neurosci. 27, 279–306.PubMedCrossRefGoogle Scholar
  59. Talamini LM, T Koch, GJ Ter Horst and J Korf (1998) Methylazoxymethanol acetate-induced abnormalities in the entorhinal cortex of the rat; parallels with morphological findings in schizophrenia.Brain Res. 789, 293–306.PubMedCrossRefGoogle Scholar
  60. Talamini LM, B Ellenbroek, T Koch and J Korf (2000) Impaired sensory gating and attention in rats with developmental abnormalities of the mesocortex. Implications for schizophrenia.Ann. NYAcad. Sci. 911, 486–494.CrossRefGoogle Scholar
  61. Venables PH (1992) Hippocampal function and schizophrenia. Experimental psychological evidence. Ann.NY Acad. Sci. 658, 111–127.CrossRefGoogle Scholar
  62. Volk DW, MC Austin, JN Pierri, AR Sampson and DA Lewis (2000) Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical γ-aminobutyric acid neurons in subjects with schizophrenia.Arch. Gen. Psychiatry 57(3), 237–245.PubMedCrossRefGoogle Scholar
  63. Waddington JL, A Lane, C Larkin and E O’Callaghan (1999) The neurodevelopmental basis of schizophrenia: clinical clues from cerebro-craniofacial dysmorphogenesis, and the roots of a lifetime trajectory of disease.Biol. Psychiatry 46(1), 31–39.PubMedCrossRefGoogle Scholar
  64. Weiss AP, D Goff, DL Schacter, T Ditman, O Freudenreich, D Henderson and S Heckers (2006) Fronto-hippocampal function during temporal context monitoring in schizophrenia.Biol. Psychiatry 60, 1268–1277.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  1. 1.Departments of Neuroscience, Psychiatry, and PsychologyUniversity of PittsburghPittsburghUSA

Personalised recommendations