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Disrupted Pattern of D2 Dopamine Receptors in the Temporal Lobe in Schizophrenia: A Postmortem Study

Disrupted Pattern of D2 Dopamine Receptors in the Temporal Lobe in Schizophrenia: A Postmortem Study Abstract Background: Anatomical substrates for the clinical efficacy of D2 dopamine receptor antagonism in ameliorating positive symptoms, including auditory hallucinations, in schizophrenia are not fully known. We previously identified a modular organization of D2 receptors unique to the temporal lobe. The dense bands of D2 receptors showed highest frequency in auditory and speech association cortices (Brodmann areas 22,39,and 42) and auditory-visual association areas (Brodmann areas 20 and 37) but were rarely found in somatosensory association regions (Brodmann area 21). Since the anatomical localization of these bands mirrors the presumed sites underlying hallucinations in schizophrenia, the modular and laminar distribution of D2 receptors was studied in the temporal cortex in the brains of schizophrenic and control subjects. Methods: Tissue obtained post mortem from 12 elderly schizophrenic subjects and 13 controls matched for age and postmortem interval was examined by quantitative receptor autoradiography for D2 receptor binding with [125I] epidepride. All regions of the temporal lobe were sampled in all cases. Results: Schizophrenic cases exhibited significantly disrupted patterns of D2 receptors in the perirhinal, superior, and inferior temporal cortices, including disrupted patterns in the modular D2 receptor bands. The schizophrenic cases had reduced concentrations of D2 receptors in the supragranular layers and elevated concentrations of D2 receptors in the granular layer in isocortical regions of the temporal lobe. This disruption does not appear to be due to long-term treatment with antipsychotic drugs and is regionally specific as there were no differences between groups for concentrations or patterns of expression in the hippocampal complex. Conclusions: Blockade of the disrupted distribution of D2 receptors in auditory and auditory-visual association cortices is a likely mechanism for the clinical efficacy of D2 antagonists in reducing hallucinations. The regionally specific, aberrant pattern of D2 receptors may be a symptom of anomalous cortical development in these regions. References 1. Angrist B, Rotrosen J, Gershon S. Differential effects of amphetamine and neuroleptics on negative vs positive symptoms in schizophrenia . Psychopharmacology . 1980;72:17-19.Crossref 2. Bowers MB. The role of drugs in the production of schizophreniform psychoses and related disorders . In: Meltzer HV, ed. Psychopharmacology: The Third Generation of Progress . New York, NY: Raven Press; 1987:819-832. 3. Snyder SH. Catecholamines in the brain as mediator of amphetamine psychosis . Arch Gen Psychiatry . 1973;130:61-67. 4. Tamminga CA, Schaffer MH, Smith RC, Davis JM. Schizophrenic symptoms improve with apomorphine . Science . 1978;200:567-568.Crossref 5. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization . Am J Psychiatry . 1991;148:1474-1486. 6. Grace AA. Cortical regulation of subcortical systems and its possible relevance to schizophrenia . J Neural Transm . 1993;91:111-134.Crossref 7. Seeman P, Bzowej NH, Guan HC, Bergeron C, Reynolds GP, Bird ED, Riederer P, Jellinger K, Tourtellote WW. Human brain D, and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's and Huntington's disease . Neuropsychopharmacology . 1987;1:5-15.Crossref 8. Gurevich EV, Bordelon Y, Shapiro R, Arnold S, Gur R, Joyce JN. Mesolimbic dopamine D3 receptors and use of antipsychotic drugs in patients with schizophrenia: a postmortem study . Arch Gen Psychiatry . 1997;54:225-232.Crossref 9. Gur RE, Jaggi JL, Shtasel DL, Ragland JD, Gur RC. Cerebral blood flow in schizophrenia . Biol Psychiatry . 1994;35:3-15.Crossref 10. Tamminga CA, Burrows GH, Chase TN, Alphs LD, Thaker GK. Dopamine neuronal tracts in schizophrenia . Ann N Y Acad Sci . 1988;537:443-450.Crossref 11. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase N, Carpenter WT. Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome . Arch Gen Psychiatry . 1992;49:522-530.Crossref 12. Wolkin A, Sanfilipo M, Angrist B, Duncan E, Wieland S, Wolf AP, Brodie JD, Copper TB, Laska E, Rostrosen JP. Acute d-amphetamine challenge in schizophrenia . Biol Psychiatry . 1994;36:317-332.Crossref 13. Shapiro RM. Regional neuropathology in schizophrenia: where are we? where are we going? Schizophr Res . 1993;10:187-239.Crossref 14. Arnold SE, Lee VM, Gur RE, Trojanowski JQ. Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia . Proc Natl Acad Sci U S A . 1991;88:10850-10854.Crossref 15. Browning MD, Dudek EM, Rapier JL, Leonard S, Freedman R. Significant reduction in synapsin but not synaptophysin specific activity in the brains of some schizophrenics . Biol Psychiatry . 1993;34:529-535.Crossref 16. Barbeau D, Liang JJ, Robitaille Y, Quiron R, Srivastava LK. Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains . Proc Natl Acad Sci U S A . 1995;92:2785-2789.Crossref 17. Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr, Jones EG. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development . Arch Gen Psychiatry . 1993;50:178-187.Crossref 18. Arnold SE, Hyman BT, Van Hoesen GW, Damasio AR. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia . Arch Gen Psychiatry . 1991;48:625-632.Crossref 19. Jacob H, Beckmann H. Prenatal development disturbances in the limbic allocortex in schizophrenics . J Neural Transm . 1986;65:154-161. 20. Jakob H, Beckmann H. Gross and histological criteria for developmental disorders in brains of schizophrenics . J R Soc Med . 1989;82:466-469. 21. Goldsmith SK, Joyce JN. D2 receptor expression in hippocampus and parahippocampal cortices of human, rat and cat in comparison with tyrosine hydroxylase immunoreactive fibers . Hippocampus . 1994;4:1-20.Crossref 22. Goldsmith S, Joyce JN. Dopamine D2 receptors are organized in bands in normal human temporal cortex . Neuroscience . 1996;74:435-451.Crossref 23. Barta PE, Pearlson GD, Powers RE, Richards S, Tune LE. Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia . Am J Psychiatry . 1990;147:1457-1462. 24. McGuire PK, Shah GMS, Murray RM. Increased blood flow in Broca's area during auditory hallucinations in schizophrenia . Lancet . 1993;342:703-706.Crossref 25. Arnold SE, Gur RE, Shapiro RM, Fisher KR, Moberg PJ, Gibney MR, Gur RC, Blackwell P, Trojanowski, JQ. Prospective clinicopathological studies of schizophrenia: accrual and assessment . Am J Psychiatry . 1995;152:731-737. 26. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised . Washington, DC: American Psychiatric Association; 1987. 27. Arnold SE, Franz BR, Trojanowski JQ. Elderly patients with schizophrenia exhibit infrequent neurodegenerative lesions . Neurobiol Aging . 1994;15:299-303.Crossref 28. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease . Cereb Cortex . 1991;1:103-116.Crossref 29. Kane JM. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry . Baltimore, Md: Williams & Wilkins; 1989:777-792. 30. Ryoo H, Joyce JN. The loss of dopamine D2 receptors varies along the rostrocaudal axis of the hippocampal complex in Alzheimer's disease . J Comp Neurol . 1994;348:94-110.Crossref 31. Murray AM, Ryoo H, Gurevich E, Joyce JN. Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain . Proc Nati Acad Sci U S A . 1994;91:11271-11275.Crossref 32. Goldsmith S, Joyce JN. Alterations in the hippocampal mossy fiber pathway in schizophrenia and Alzheimer's disease . Biol Psychiatry . 1995;37:122-126.Crossref 33. Artymyshyn R, Smith A, Wolfe BB. The use of 3H standards in 125I autoradiography . J Neurosci Methods . 1990;32:185-192.Crossref 34. Roberts SJ, Hanaway J. Atlas of the Human Brain in Section . Philadelphia, Pa: Lea & Febiger; 1971. 35. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoki A, Bunney WE Jr, Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics . Arch Gen Psychiatry . 1995;52:258-266.Crossref 36. Meador-Woodruff JH, Grandy DK, Van Tol HHM, Damask SP, Little KY, Civelli O, Watson SJ. Dopamine receptor gene expression in the human medial temporal lobe . Neuropsychopharmacology . 1994;10:239-248.Crossref 37. Rakic P. Mode of cell migration to the superficial layers of the fetal monkey neocortex . J Comp Neurol . 1972;145:61-84.Crossref 38. Reinoso BS, Undie AS, Levit P. Dopamine receptors mediate differential morphological effects on cerebral cortical neurons in vitro . J Neurosci Res . 1996;43:439-453.Crossref 39. Swarzenski BC, Tang L, Oh YJ, O'Malley KL, Todd RD. Morphogenic potentials of D2, D3, and D4 dopamine receptors revealed in transfected neuronal cell lines . Proc Natl Acad Sci U S A . 1994;91:649-653.Crossref 40. Weinberger DR, Berman KF, Illowsky BP. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia, III . Arch Gen Psychiatry . 1988;45:609-615.Crossref 41. Stabenau JR, Pollin W. Heredity and environment in schizophrenia, revisited: the contribution of twin and high-risk studies . J Nerv Ment Dis . 1993;181:290-297.Crossref 42. Shenton ME, Kikinis R, Jolesz FA, Pollak SD, Le May M, Wible CG, Hokama H, Martin J, Colemean M, McCarley RW. Abnormalities of the left temporal lobe and thought disorder in schizophrenia . N Engl J Med . 1992;327:604-612.Crossref 43. McCarley RW, Shenton ME, O'Donnell BF, Gaux SF, Kikinis R, Nestor G, Jolesz FA. Auditory 300 abnormalities and left superior temporal gyrus volume reduction in schizophrenia . Arch Gen Psychiatry . 1993;50:190-197.Crossref 44. Penfield W, Perot P. The brains record of auditory and visual experience . Brain . 1963;86:595-696.Crossref 45. Joyce JN. The dopamine hypothesis of schizophrenia: limbic interactions with serotonin and norepinephrine . Psychopharmacology . 1993;112( (suppl) ):S16-S34.Crossref 46. Cleghorn JM, Franco S, Szechtman B, Kaplan RD, Szechtman H, Brown GM, Nahmias C, Garnett ES. Toward a brain map of auditory hallucinations . Am J Psychiatry . 1992;149:1062-1069. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of General Psychiatry American Medical Association

Disrupted Pattern of D2 Dopamine Receptors in the Temporal Lobe in Schizophrenia: A Postmortem Study

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Publisher
American Medical Association
Copyright
Copyright © 1997 American Medical Association. All Rights Reserved.
ISSN
0003-990X
eISSN
1598-3636
DOI
10.1001/archpsyc.1997.01830190077008
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Abstract

Abstract Background: Anatomical substrates for the clinical efficacy of D2 dopamine receptor antagonism in ameliorating positive symptoms, including auditory hallucinations, in schizophrenia are not fully known. We previously identified a modular organization of D2 receptors unique to the temporal lobe. The dense bands of D2 receptors showed highest frequency in auditory and speech association cortices (Brodmann areas 22,39,and 42) and auditory-visual association areas (Brodmann areas 20 and 37) but were rarely found in somatosensory association regions (Brodmann area 21). Since the anatomical localization of these bands mirrors the presumed sites underlying hallucinations in schizophrenia, the modular and laminar distribution of D2 receptors was studied in the temporal cortex in the brains of schizophrenic and control subjects. Methods: Tissue obtained post mortem from 12 elderly schizophrenic subjects and 13 controls matched for age and postmortem interval was examined by quantitative receptor autoradiography for D2 receptor binding with [125I] epidepride. All regions of the temporal lobe were sampled in all cases. Results: Schizophrenic cases exhibited significantly disrupted patterns of D2 receptors in the perirhinal, superior, and inferior temporal cortices, including disrupted patterns in the modular D2 receptor bands. The schizophrenic cases had reduced concentrations of D2 receptors in the supragranular layers and elevated concentrations of D2 receptors in the granular layer in isocortical regions of the temporal lobe. This disruption does not appear to be due to long-term treatment with antipsychotic drugs and is regionally specific as there were no differences between groups for concentrations or patterns of expression in the hippocampal complex. Conclusions: Blockade of the disrupted distribution of D2 receptors in auditory and auditory-visual association cortices is a likely mechanism for the clinical efficacy of D2 antagonists in reducing hallucinations. The regionally specific, aberrant pattern of D2 receptors may be a symptom of anomalous cortical development in these regions. References 1. Angrist B, Rotrosen J, Gershon S. Differential effects of amphetamine and neuroleptics on negative vs positive symptoms in schizophrenia . Psychopharmacology . 1980;72:17-19.Crossref 2. Bowers MB. The role of drugs in the production of schizophreniform psychoses and related disorders . In: Meltzer HV, ed. Psychopharmacology: The Third Generation of Progress . New York, NY: Raven Press; 1987:819-832. 3. Snyder SH. Catecholamines in the brain as mediator of amphetamine psychosis . Arch Gen Psychiatry . 1973;130:61-67. 4. Tamminga CA, Schaffer MH, Smith RC, Davis JM. Schizophrenic symptoms improve with apomorphine . Science . 1978;200:567-568.Crossref 5. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization . Am J Psychiatry . 1991;148:1474-1486. 6. Grace AA. Cortical regulation of subcortical systems and its possible relevance to schizophrenia . J Neural Transm . 1993;91:111-134.Crossref 7. Seeman P, Bzowej NH, Guan HC, Bergeron C, Reynolds GP, Bird ED, Riederer P, Jellinger K, Tourtellote WW. Human brain D, and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's and Huntington's disease . Neuropsychopharmacology . 1987;1:5-15.Crossref 8. Gurevich EV, Bordelon Y, Shapiro R, Arnold S, Gur R, Joyce JN. Mesolimbic dopamine D3 receptors and use of antipsychotic drugs in patients with schizophrenia: a postmortem study . Arch Gen Psychiatry . 1997;54:225-232.Crossref 9. Gur RE, Jaggi JL, Shtasel DL, Ragland JD, Gur RC. Cerebral blood flow in schizophrenia . Biol Psychiatry . 1994;35:3-15.Crossref 10. Tamminga CA, Burrows GH, Chase TN, Alphs LD, Thaker GK. Dopamine neuronal tracts in schizophrenia . Ann N Y Acad Sci . 1988;537:443-450.Crossref 11. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase N, Carpenter WT. Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome . Arch Gen Psychiatry . 1992;49:522-530.Crossref 12. Wolkin A, Sanfilipo M, Angrist B, Duncan E, Wieland S, Wolf AP, Brodie JD, Copper TB, Laska E, Rostrosen JP. Acute d-amphetamine challenge in schizophrenia . Biol Psychiatry . 1994;36:317-332.Crossref 13. Shapiro RM. Regional neuropathology in schizophrenia: where are we? where are we going? Schizophr Res . 1993;10:187-239.Crossref 14. Arnold SE, Lee VM, Gur RE, Trojanowski JQ. Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia . Proc Natl Acad Sci U S A . 1991;88:10850-10854.Crossref 15. Browning MD, Dudek EM, Rapier JL, Leonard S, Freedman R. Significant reduction in synapsin but not synaptophysin specific activity in the brains of some schizophrenics . Biol Psychiatry . 1993;34:529-535.Crossref 16. Barbeau D, Liang JJ, Robitaille Y, Quiron R, Srivastava LK. Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains . Proc Natl Acad Sci U S A . 1995;92:2785-2789.Crossref 17. Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr, Jones EG. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development . Arch Gen Psychiatry . 1993;50:178-187.Crossref 18. Arnold SE, Hyman BT, Van Hoesen GW, Damasio AR. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia . Arch Gen Psychiatry . 1991;48:625-632.Crossref 19. Jacob H, Beckmann H. Prenatal development disturbances in the limbic allocortex in schizophrenics . J Neural Transm . 1986;65:154-161. 20. Jakob H, Beckmann H. Gross and histological criteria for developmental disorders in brains of schizophrenics . J R Soc Med . 1989;82:466-469. 21. Goldsmith SK, Joyce JN. D2 receptor expression in hippocampus and parahippocampal cortices of human, rat and cat in comparison with tyrosine hydroxylase immunoreactive fibers . Hippocampus . 1994;4:1-20.Crossref 22. Goldsmith S, Joyce JN. Dopamine D2 receptors are organized in bands in normal human temporal cortex . Neuroscience . 1996;74:435-451.Crossref 23. Barta PE, Pearlson GD, Powers RE, Richards S, Tune LE. Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia . Am J Psychiatry . 1990;147:1457-1462. 24. McGuire PK, Shah GMS, Murray RM. Increased blood flow in Broca's area during auditory hallucinations in schizophrenia . Lancet . 1993;342:703-706.Crossref 25. Arnold SE, Gur RE, Shapiro RM, Fisher KR, Moberg PJ, Gibney MR, Gur RC, Blackwell P, Trojanowski, JQ. Prospective clinicopathological studies of schizophrenia: accrual and assessment . Am J Psychiatry . 1995;152:731-737. 26. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised . Washington, DC: American Psychiatric Association; 1987. 27. Arnold SE, Franz BR, Trojanowski JQ. Elderly patients with schizophrenia exhibit infrequent neurodegenerative lesions . Neurobiol Aging . 1994;15:299-303.Crossref 28. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease . Cereb Cortex . 1991;1:103-116.Crossref 29. Kane JM. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry . Baltimore, Md: Williams & Wilkins; 1989:777-792. 30. Ryoo H, Joyce JN. The loss of dopamine D2 receptors varies along the rostrocaudal axis of the hippocampal complex in Alzheimer's disease . J Comp Neurol . 1994;348:94-110.Crossref 31. Murray AM, Ryoo H, Gurevich E, Joyce JN. Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain . Proc Nati Acad Sci U S A . 1994;91:11271-11275.Crossref 32. Goldsmith S, Joyce JN. Alterations in the hippocampal mossy fiber pathway in schizophrenia and Alzheimer's disease . Biol Psychiatry . 1995;37:122-126.Crossref 33. Artymyshyn R, Smith A, Wolfe BB. The use of 3H standards in 125I autoradiography . J Neurosci Methods . 1990;32:185-192.Crossref 34. Roberts SJ, Hanaway J. Atlas of the Human Brain in Section . Philadelphia, Pa: Lea & Febiger; 1971. 35. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoki A, Bunney WE Jr, Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics . Arch Gen Psychiatry . 1995;52:258-266.Crossref 36. Meador-Woodruff JH, Grandy DK, Van Tol HHM, Damask SP, Little KY, Civelli O, Watson SJ. Dopamine receptor gene expression in the human medial temporal lobe . Neuropsychopharmacology . 1994;10:239-248.Crossref 37. Rakic P. Mode of cell migration to the superficial layers of the fetal monkey neocortex . J Comp Neurol . 1972;145:61-84.Crossref 38. Reinoso BS, Undie AS, Levit P. Dopamine receptors mediate differential morphological effects on cerebral cortical neurons in vitro . J Neurosci Res . 1996;43:439-453.Crossref 39. Swarzenski BC, Tang L, Oh YJ, O'Malley KL, Todd RD. Morphogenic potentials of D2, D3, and D4 dopamine receptors revealed in transfected neuronal cell lines . Proc Natl Acad Sci U S A . 1994;91:649-653.Crossref 40. Weinberger DR, Berman KF, Illowsky BP. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia, III . Arch Gen Psychiatry . 1988;45:609-615.Crossref 41. Stabenau JR, Pollin W. Heredity and environment in schizophrenia, revisited: the contribution of twin and high-risk studies . J Nerv Ment Dis . 1993;181:290-297.Crossref 42. Shenton ME, Kikinis R, Jolesz FA, Pollak SD, Le May M, Wible CG, Hokama H, Martin J, Colemean M, McCarley RW. Abnormalities of the left temporal lobe and thought disorder in schizophrenia . N Engl J Med . 1992;327:604-612.Crossref 43. McCarley RW, Shenton ME, O'Donnell BF, Gaux SF, Kikinis R, Nestor G, Jolesz FA. Auditory 300 abnormalities and left superior temporal gyrus volume reduction in schizophrenia . Arch Gen Psychiatry . 1993;50:190-197.Crossref 44. Penfield W, Perot P. The brains record of auditory and visual experience . Brain . 1963;86:595-696.Crossref 45. Joyce JN. The dopamine hypothesis of schizophrenia: limbic interactions with serotonin and norepinephrine . Psychopharmacology . 1993;112( (suppl) ):S16-S34.Crossref 46. Cleghorn JM, Franco S, Szechtman B, Kaplan RD, Szechtman H, Brown GM, Nahmias C, Garnett ES. Toward a brain map of auditory hallucinations . Am J Psychiatry . 1992;149:1062-1069.

Journal

Archives of General PsychiatryAmerican Medical Association

Published: Jul 1, 1997

References

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