본문 바로가기
KERD
논문KCI 등재

Hippocampal Dysregulation of Dopamine System Activity as a Pathophysiological Basis for Psychosis in Schizophrenia

2

조회

0

다운로드

3

인용

0

참고문헌

키워드

초록

For over 40 years, the dominant hypothesis of schizophrenia has been based on deficits leading to overstimulation by dopamine. In recent years, however, there has been a shift from a primary dopamine deficit to a dysfunction involving cortical regulation of the dopamine system. Current research represents a remarkable convergence of both clinical research and basic animal studies into the pathophysiology of schizophrenia. Thus, clinical studies have detailed a dopamine system that is hyper-responsive to inputs, and hyperactivity in the hippocampus that correlates with psychosis. Experiments in developmental animal models have shown that hyperactivity within the hippocampus subiculum drives an increase in dopamine neuron population activity that underlies the abnormally high responsivity of the dopamine system to stimuli. In both human studies and animal models, there is a corresponding loss of parvalbumin interneurons in the prefrontal cortex and the hippocampus, and this correlates with the loss of evoked gamma oscillatory rhythms in both subjects. Therefore, a model emerges in which a loss of activity within a selective interneuron population as observed postmortem in schizophrenia patients as well as in a developmental animal model of schizophrenia leads to disorganized hyper-activity within the hippocampus. This in turn renders the dopamine system hyper-responsive to stimuli, causing an inordinate attribution of attention and salience to all stimuli independent of their functional significance. These studies suggest that a more effective therapeutic strategy would involve restoration of hippocampal activity states via modulation of interneuron regulation.

Abstract

For over 40 years, the dominant hypothesis of schizophrenia has been based on deficits leading to overstimulation by dopamine. In recent years, however, there has been a shift from a primary dopamine deficit to a dysfunction involving cortical regulation of the dopamine system. Current research represents a remarkable convergence of both clinical research and basic animal studies into the pathophysiology of schizophrenia. Thus, clinical studies have detailed a dopamine system that is hyper-responsive to inputs, and hyperactivity in the hippocampus that correlates with psychosis. Experiments in developmental animal models have shown that hyperactivity within the hippocampus subiculum drives an increase in dopamine neuron population activity that underlies the abnormally high responsivity of the dopamine system to stimuli. In both human studies and animal models, there is a corresponding loss of parvalbumin interneurons in the prefrontal cortex and the hippocampus, and this correlates with the loss of evoked gamma oscillatory rhythms in both subjects. Therefore, a model emerges in which a loss of activity within a selective interneuron population as observed postmortem in schizophrenia patients as well as in a developmental animal model of schizophrenia leads to disorganized hyper-activity within the hippocampus. This in turn renders the dopamine system hyper-responsive to stimuli, causing an inordinate attribution of attention and salience to all stimuli independent of their functional significance. These studies suggest that a more effective therapeutic strategy would involve restoration of hippocampal activity states via modulation of interneuron regulation.

참고문헌 (85)

  1. Wu EQ, "The economic burden of schizophrenia in the United States in 2002", J Clin Psychiatry, 66, pp.1122~1129 (2005)
  2. Carlsson A, "Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain", Acta Pharmacol Toxicol (Copenh), 20, pp.140~144 (1963)
  3. Seeman P, "Antipsychotic drug doses and neuroleptic", dopamine receptors, 1976, pp.261, 717~719
  4. Creese I, "Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs", Science, 192, pp.481~483 (1976)
  5. Angrist B, "Amphetamine psychosis: behavioral and biochemical aspects", J Psychiatr Res, 11, pp.13~23 (1974)
  6. Friedman A, "Psychotic complications of long-term levodopa treatment of Parkinson's disease", Acta Neurol Scand, 84, pp.111~113 (1991)
  7. Giladi N, "Risk factors for dementia, depression and psychosis in long-standing Parkinson's disease", J Neural Transm, 107, pp.59~71 (2000)
  8. Angrist B, "Clinical studies with dopamine-receptor stimulants", Psychopharmacologia, 44, pp.273~280 (1975)
  9. van Rossum JM, "The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs", Arch Int Pharmacodyn Ther, 160, pp.492~494 (1966)
  10. Hollister LE, "Treatment of chronic schizophrenic reactions with reserpine", Ann N Y Acad Sci, 61, pp.92~100 (1955)
  11. Beuger M, "Dopamine turnover in schizophrenia before and after haloperidol withdrawal. CSF, plasma, and urine studies", Neuropsychopharmacology, 15, pp.75~86 (1996)
  12. Post RM, "Cerebrospinal fluid amine metabolites in acute schizophrenia", Arch Gen Psychiatry, 32, pp.1063~1069 (1975)
  13. van Kammen DP, "Dopamine metabolism in the cerebrospinal fluid of drug-free schizophrenic patients with and without cortical atrophy", Arch Gen Psychiatry, 43, pp.978~983 (1986)
  14. Sharp T, "A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis", Brain Res, 401, pp.322~330 (1987)
  15. Johnstone EC, "Mechanism of the antipsychotic effect in the treatment of acute schizophrenia", Lancet, 22, pp.848~851 (1978)
  16. Agid O, "Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected", Arch Gen Psychiatry, 60, pp.1228~1235 (2003)
  17. Shoptaw SJ, "Treatment for amphetamine psychosis", Cochrane Database Syst Rev, (1) (2009)
  18. Laruelle M, "Increased dopamine transmission in schizophrenia: relationship to illness phases", Biol Psychiatry, 46, pp.56~72 (1999)
  19. Grace AA, "Gating of information flow within the limbic system and the pathophysiology of schizophrenia", Brain Res Brain Res Rev, 31, pp.330~341 (2000)
  20. Javitt DC, "Recent advances in the phencyclidine model of schizophrenia", Am J Psychiatry, 148, pp.1301~1308 (1991)
  21. Luby ED, "Model psychoses and schizophrenia", Am J Psychiatry, 119, pp.61~67 (1962)
  22. Weinberger DR, "Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence", Arch Gen Psychiatry, 43, pp.114~124 (1986)
  23. Berman KF, "Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. II. Role of neuroleptic treatment, attention, and mental effort", Arch Gen Psychiatry, 43, pp.126~135 (1986)
  24. Kovelman JA, "A neurohistological correlate of schizophrenia", Biol Psychiatry, 19, pp.1601~1621 (1984)
  25. Conrad AJ, "Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon", Arch Gen Psychiatry, 48, pp.413~417 (1991)
  26. Suddath RL, "Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia", N Engl J Med, 322, pp.789~794 (1990)
  27. Lee AL, "Stress and depression: possible links to neuron death in the hippocampus", Bipolar Disord, 4, pp.117~128 (2002)
  28. Sapolsky RM, "Hippocampal damage associated with prolonged glucocorticoid exposure in primates", J Neurosci, 10, pp.2897~2902 (1990)
  29. Sapolsky RM, "Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders", Arch Gen Psychiatry, 57, pp.925~935 (2000)
  30. Benes FM, "The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia", J Psychiatr Res, 31, pp.257~275 (1997)
  31. Susser E, "Schizophrenia after prenatal famine. Further evidence", Arch Gen Psychiatry, 53, pp.25~31 (1996)
  32. McDonald C, "Early and late environmental risk factors for schizophrenia", Brain Res Brain Res Rev, 31, pp.130~137 (2000)
  33. Lipska BK, "Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia", Neuropsychopharmacology, 9, pp.67~75 (1993)
  34. Lipska BK, "Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine", Psychopharmacology (Berl), 122, pp.35~43 (1995)
  35. Lipska BK, "Neonatal damage of the ventral hippocampus impairs working memory in the rat", Neuropsychopharmacology, 27, pp.47~54 (2002)
  36. Gottesman II, "Schizophrenia genesis: The origins of madness" (1991), Freeman
  37. Grace AA, "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", pp.123~157 (1998), American Psychological Association Press
  38. Moore H, "A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia", Biol Psychiatry, 60, pp.253~264 (2006)
  39. Pilowsky LS, "Schizophrenia: a neurodevelopmental perspective", Neuropsychopharmacology, 9, pp.83~91 (1993)
  40. Harrison PJ, "The neuropathology of schizophrenia. A critical review of the data and their interpretation", Brain, 122, pp.593~624 (1999)
  41. Moore H, "Anatomical changes in limbic structures produced by methylazoxymethanol acetate (MAM) during brain development are associated with changes in physiological interactions among afferents to the nucleus accumbens", Soc Neurosci Abstr, 23, pp.2378~ (1997)
  42. Flagstad P, "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", Neuropsychopharmacology, 29, pp.2052~2064 (2004)
  43. Gourevitch R, "Working memory deficits in adult rats after prenatal disruption of neurogenesis", Behav Pharmacol, 15, pp.287~292 (2004)
  44. Le Pen G, "Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat", Neuroscience, 143, pp.395~405 (2006)
  45. Lodge DJ, "A reduction in hippocampal and prefrontal cortical gamma oscillatory activity is associated with a decrease in parvalbumin interneurons in the mam model of schizophrenia. Society for Neuroscience, Neuroscience Meeting Planner", Society for Neuroscience, Neuroscience Meeting Planner, Program No 657.2, ~ (2008)
  46. Talamini LM, "Interruptions of early cortical development affect limbic association areas and social behaviour in rats; possible relevance for neurodevelopmental disorders", Brain Res, 847, pp.105~120 (1999)
  47. Fiore M, "Stampachiacchiere B, Aloe L. Impaired brain development in the rat following prenatal exposure to methylazoxymethanol acetate at gestational day 17 and neurotrophin distribution", Neuroreport, 15, pp.1791~1795 (2004)
  48. Malaspina D, "SPECT study of visual fixation in schizophrenia and comparison subjects", Biol Psychiatry, 46, pp.89~93 (1999)
  49. Heckers S, "Neuroimaging studies of the hippocampus in schizophrenia", Hippocampus, 11, pp.520~528 (2001)
  50. Kegeles LS, "Hippocampal pathology in schizophrenia: magnetic resonance imaging and spectroscopy studies", Psychiatry Res, 98, pp.163~175 (2000)
  51. Medoff DR, "Probing the human hippocampus using rCBF: contrasts in schizophrenia", Hippocampus, 11, pp.543~550 (2001)
  52. Meyer-Lindenberg AS, "Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia", Arch Gen Psychiatry, 62, pp.379~386 (2005)
  53. Lahti AC, "Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia", Neuropsychopharmacology, 31, pp.221~230 (2006)
  54. Weiss AP, "Fronto-hippocampal function during temporal context monitoring in schizophrenia", Biol Psychiatry, 60, pp.1268~1277 (2006)
  55. Silbersweig DA, "A functional neuroanatomy of hallucinations in schizophrenia", Nature, 378, pp.176~179 (1995)
  56. Lahti AC, "Ketamine activates psychosis and alters limbic blood flow in schizophrenia", Neuroreport, 6, pp.869~872 (1995)
  57. Grace AA, "The control of firing pattern in nigral dopamine neurons: single spike firing", J Neurosci, 4, pp.2866~2876 (1984)
  58. Grace AA, "Opposing effects of striatonigral feedback pathways on midbrain dopamine cell activity", Brain Res, 333, pp.271~284 (1985)
  59. Floresco SB, "Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons", J Neurosci, 21, pp.4915~4922 (2001)
  60. Floresco SB, "Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission", Nat Neurosci, 6, pp.968~973 (2003)
  61. Schultz W, "The phasic reward signal of primate dopamine neurons", Adv Pharmacol, 42, pp.686~690 (1998)
  62. Grace AA, "The control of firing pattern in nigral dopamine neurons: burst firing", J Neurosci, 4, pp.2877~2890 (1984)
  63. Lodge DJ, "The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation", Neuropsychopharmacology, 31, pp.1356~1361 (2006)
  64. Mayer ML, "Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones", Nature, 309, pp.261~263 (1984)
  65. Jarrard LE, "What does the hippocampus really do?", Behav Brain Res, 71, pp.1~10 (1995)
  66. Maren S, "Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in the acquisition and expression of Pavlovian fear conditioning in rats", Behav Neurosci, 113, pp.283~290 (1999)
  67. Sharp PE, "Complimentary roles for hippocampal versus subicular", entorhinal place cells in coding place, context, and events, 1999, pp.9, 432~443
  68. Fanselow MS, "Contextual fear, gestalt memories and the hippocampus", Behav Brain Res, 110, pp.73~81 (2000)
  69. Lodge DJ, "Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia", J Neurosci, 27, pp.11424~11430 (2007)
  70. Laruelle M, "Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies", J Psychopharmacol, 13, pp.358~371 (1999)
  71. Laruelle M, "Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects", Proc Natl Acad Sci USA, 93, pp.9235~9240 (1996)
  72. Zhang ZJ, "A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia", Schizophr Res, 55, pp.1~10 (2002)
  73. Lewis DA, "Laminaspecific deficits in parvalbumin-immunoreactive varicosities in the prefrontal cortex of subjects with schizophrenia: evidence for fewer projections from the thalamus", Am J Psychiatry, 158, pp.1411~1422 (2001)
  74. Vida I, "Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates", Neuron, 49, pp.107~117 (2006)
  75. Bartos M, "Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks", Nat Rev Neurosci, 8, pp.45~56 (2007)
  76. Fuchs EC, "Recruitment of parvalbumin- positive interneurons determines hippocampal function and associated behavior", Neuron, 53, pp.591~604 (2007)
  77. Tukker JJ, "Cell type-specific tuning of hippocampal interneuron firing during gamma oscillations in vivo", J Neurosci, 27, pp.8184~8189 (2007)
  78. Buzsá0ki G, "Neuronal oscillations in cortical networks", Science, 304, pp.1926~1929 (2004)
  79. González-Hernández JA, "Induced oscillations and the distributed cortical sources during the Wisconsin card sorting test performance in schizophrenic patients: new clues to neural connectivity", Int J Psychophysiol, 48, pp.11~24 (2003)
  80. Gallinat J, "Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing", Clin Neurophysiol, 115, pp.1863~1874 (2004)
  81. Cho RY, "Impairments in gamma band synchronization and context processing in schizophrenia", Schizophr Bull, 31, pp.450~451 (2005)
  82. Basar-Eroglu C, "Working memory related gamma oscillations in schizophrenia patients", Int J Psychophysiol, 64, pp.39~45 (2007)
  83. Lodge DJ, "A loss of parvalbumincontaining interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia", J Neurosci, 29, pp.2344~2354 (2009)
  84. Jones RS, "Basket-like interneurones in layer II of the entorhinal cortex exhibit a powerful NMDA-mediated synaptic excitation", Neurosci Lett, 149, pp.35~39 (1993)
  85. Buhl EH, "Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro", Hippocampus, 6, pp.294~305 (1996)

관련 논문AI추천

이 간행물의 다른 논문 (7건)