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Beyond the Dopamine Hypothesis

The Neurochemical Pathology of Schizophrenia

Published online by Cambridge University Press:  02 January 2018

G. P. Reynolds
G. P. Reynolds*
Affiliation:
Department of Pathology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH
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Abstract

The dopamine hypothesis still provides a valuable approach to the study of schizophrenia and its treatment by drugs. Although the neuroleptic drugs appear to act via an inhibition of dopamine receptors, measurements of dopamine metabolites in vivo, or of the transmitter and its receptors in postmortem brain tissue, do not provide unequivocal evidence of a hyperactivity of dopaminergic neurotransmission in the disease. Nevertheless, increased dopamine function might be a consequence of a primary neuronal abnormality in another system. Recent imaging studies and neuropathological reports suggest that, in some patients, there may be a deficit and/or disturbance of neurons in certain temporal limbic regions, and this is supported by some neurochemical investigations, particularly of neuropeptide and amino-acid transmitter systems. A loss of such neurons could conceivably lead to a disinhibition of limbic dopamine neurons, providing the means whereby neuroleptic drug treatment might ameliorate the effects of a neuronal deficit in schizophrenia.

Type
Review Article
Information
The British Journal of Psychiatry , Volume 155 , Issue 3 , September 1989 , pp. 305 - 316
Copyright
Copyright © Royal College of Psychiatrists, 1989 

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References

Andreasen, N. C., Olsen, S. A., Dennert, J. W., et al (1982) Ventricular enlargement in schizophrenia: relationship to positive and negative symptoms. American Journal of Psychiatry, 139, 297–302.Google Scholar
Bacopoulos, N. G., Hattox, S. E. & Roth, R. H. (1979a) 3, 4-Dihydroxyphenylacetic acid and homovanillic acid in rat plasma: possible indicators of central dopaminergic activity. European Journal of Pharmacology, 56, 225–236.Google Scholar
Bacopoulos, N. G., Spokes, E. G., Bird, E. D., et al(1979b) Antipsychotic drug action in schizophrenic patients: effects on cortical dopamine metabolism after long-term treatment. Science, 205, 1405–1407.Google Scholar
Bannon, M. J. & Roth, R. H. (1983) Pharmacology of mesocortical dopamine neurons. Pharmacological Reviews, 35, 53–68.Google Scholar
Benes, F. M., Davidson, J. & Bird, E. D. (1986) Quantitative cytoarchitectural studies of the cerebral cortex in schizophrenics. Archives of General Psychiatry, 44, 1017–1021.Google Scholar
Bird, E. D., Spokes, E. G. S., Barnes, J., et al (1978) Glutamic acid decarboxylase in schizophrenia. Lancet, ii, 156.CrossRefGoogle Scholar
Bird, E. D., Spokes, E. G. S. & Iversen, L. L. (1979) Increased dopamine concentrations in limbic areas of brain from patients dying with schizophrenia. Brain, 102, 347–360.CrossRefGoogle ScholarPubMed
Bissette, G., Nemeroff, C. B. & Mackay, A. V. P. (1986) Peptides in schizophrenia In Progress in Brain Research, vol. 66 (eds P. C. Emson, M. Rosser & M. Tohyama). Amsterdam: Elsevier.Google Scholar
Bogerts, B., Meertz, C. & Schonfeldt-Bausch, R. (1985) Basal ganglia and limbic system pathology in schizophrenia: a morphometric study. Archives of General Psychiatry, 42, 784–791.Google Scholar
Bowers, M. B. (1974) Central dopamine turnover in schizophrenic syndromes. Archives of General Psychiatry, 31, 50–54.Google Scholar
Bowers, M. B. & Swigar, M. E. (1987) Acute psychosis and plasma catecholamine metabolites. Archives of General Psychiatry, 44, 190.Google Scholar
Bracha, H. S. (1987) Asymmetric rotational (circling) behavior, a dopamine-related asymmetry: preliminary findings in unmedicated and never-medicated schizophrenic patients. Biological Psychiatry, 22, 995–1003.CrossRefGoogle ScholarPubMed
Brown, R., Colter, N., Corsellis, J. A. N., et al (1986) Postmortem evidence of structural brain changes in schizophrenia. Archives of General Psychiatry, 43, 36–42.CrossRefGoogle ScholarPubMed
Christie, M. J., Rowe, P. J. & Beart, P. M. (1986) Effects of excitotoxic lesions in the medial prefrontal cortex on cortical and subcortical catecholamine turnover in the rat. Journal of Neurochemistry, 47, 1593–1597.Google Scholar
Cleghorn, J. M. & Brown, G. M. (1988) Neuroendocrine studies in schizophrenia In Receptors and Ligands in Psychiatry (eds A. K. Sen T. A Lee). Cambridge: Cambridge University Press.Google Scholar
Clow, A., Theodorou, A., Jenner, P., et al (1980) Changes in rat striatal dopamine turnover and receptor activity during one year's neuroleptic administration. European Journal of Pharmacology, 63, 135–144.Google Scholar
Crawley, J. C., Crow, T. J., Johnstone, E. C., et al (1986) Dopamine D-2 receptors in schizophrenia studied in vivo. Lancet, ii, 224–225.Google Scholar
Creese, I., Burt, D. R. & Snyder, S. H. (1975) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science, 192, 481–483.Google Scholar
Cross, A. J., Crow, T. J. & Owen, F. (1979) Gamma-aminobutyric acid in the brain in schizophrenia. Lancet, i, 560–561.Google Scholar
Crow, T. J., Owen, F., Cross, A. J., et al (1981) Neurotransmitter enzymes and receptors in postmortem brain in schizophrenia; evidence that an increase in D2 receptors is associated with the type I syndrome In Transmitter Biochemistry of Human Brain Tissue (eds P. Riederer & E. Usdin). London: Macmillan.Google Scholar
Crow, T. J., Brown, R., Bruton, C. J., et al (1988) Lateral asymmetry of temporal horn enlargement in schizophrenia. Neuroscience Letters (suppl. 32), S58.Google Scholar
Czudek, C. & Reynolds, G. P. (1989) [3H]GBR 12935 binding to the dopamine uptake site in postmortem brain tissue in schizophrenia. Journal of Neural Transmission (in press).CrossRefGoogle Scholar
Davidson, M., Giordani, A. B., Mohs, R. C., et al (1987) Short-term haloperidol administration acutely elevates human plasma homovanillic acid concentration. Archives of General Psychiatry, 44, 189–190.Google Scholar
Davidson, M., & Davis, K. L. (1988) A comparison of plasma homovanillic acid concentrations in schizophrenic patients and normal controls. Archives of General Psychiatry, 45, 561–563.Google Scholar
Davila, R., Manero, E., Zumarraga, M., et al (1988) Plasma homovanillic acid as a predictor of response to neuroleptics. Archives of General Psychiatry, 45, 564–567.CrossRefGoogle ScholarPubMed
Davis, K. L., Davidson, M., Mohs, R. C., et al (1985) Plasma homovanillic acid concentration and the severity of schizophrenic illness. Science, 227, 1601–1602.CrossRefGoogle ScholarPubMed
Davison, K. (1987) Organic and toxic concomitants of schizophrenia: association or chance? In Biological Perspectives of Schizophrenia (eds H. Helmchen A F. A. Henn). Chichester: Wiley.Google Scholar
Deakin, J. F. W., Slater, P., Simpson, M. D. C., et al (1989) Frontal cortical and left temporal glutamatergic dysfunction of schizophrenia. Journal of Neurochemistry, 52, 1781–1786.Google Scholar
DeLisi, L. E., Wise, C. D., Bridge, T. P., et al (1982) Monoamine oxidase and schizophrenia In Biological Markers in Psychiatry and Neurology (eds E. Usdin & I. Hanin). Oxford: Pergamon.Google Scholar
Doran, A. R., Boronow, J., Weinberger, D. R., et al (1987) Structural brain pathology in schizophrenia revisited. Neuropsychopharmacology, 1, 25–32.CrossRefGoogle ScholarPubMed
Early, T. S., Reiman, E. M., Raichle, M. E., et al (1987) Left globus pallidus abnormality in never-mediated patients with schizophrenia. Proceedings of the National Academy of Sciences (USA), 84, 561–563.CrossRefGoogle Scholar
Elsworth, J. D., Leahy, D. J., Roth, R. H., et al (1987) Homovanillic acid concentrations in brain, CSF and plasma as indicators of central dopamine function in primates. Journal of Neural Transmission, 68, 51–62.Google Scholar
Falkai, P., Bogerts, B. & Rozumek, M. (1988) Limbic pathology in schizophrenia: the entorhinal region-a morphometric study. Biological Psychiatry, 24, 515–521.Google Scholar
Farde, L., Wiesel, F.-A., Hall, H., et al (1987) No D2 receptor increase in PET study of schizophrenia. Archives of General Psychiatry, 44, 671–672.Google Scholar
Farmery, S. M., Owen, F., Poulter, M., et al (1985) Reduced high affinity cholecystokinin binding in hippocampus and frontal cortex of schizophrenic patients. Life Sciences, 36, 473–477.Google Scholar
Ferrier, I. N., Roberts, G. W., Crow, T. J., et al (1983) Reduced cholecystokinin-like and somatostatin-like immunoreactivity in limbic lobe is associated with negative symptoms in schizophrenia. Life Sciences, 33, 475–482.Google Scholar
Fibiger, H. C. & Lloyd, K. G. (1984) Neurobiological substrates of tardive dyskinesia: the GABA hypothesis. Trends in Neurosciences, 7, 462–464.Google Scholar
Flor-Henry, P. (1969) Psychosis and temporal lobe epilepsy: a controlled investigation. Epilepsia, 10, 363–395.Google Scholar
Gloor, P. (1986) Role of the human limbic system in perception, memory and affect In The Limbic System (eds B. K. Doane & K. E. Livingston). New York: Raven Press.Google Scholar
Gunne, L. M., Haogstrom, J. & Sjoquist, B. (1984) Association with persistent neuroleptic induced dyskinesia of regional changes in brain GABA synthesis. Nature, 309, 347–349.Google Scholar
Heath, R. G. (1954) Studies in Schizophrenia. Cambridge: Harvard University Press.Google Scholar
Hemsley, D. R. (1987) An experimental psychological model for schizophrenia In Search for the Causes of Schizophrenia (eds H. Haefner, W. F. Gattaz & W. Janzarik). Heidelberg: Springer.Google Scholar
Hess, E. J., Bracha, H. S., Kleinman, J. E., et al (1987) Dopamine receptor subtype imbalance in schizophrenia. Life Sciences, 40, 1487–1497.Google Scholar
Hokfelt, T., Rehfeld, J. F., Skirboll, L., et al (1980) Evidence for coexistence of dopamine and CCK in mesolimbic neurons. Nature, 285, 476–478.Google Scholar
Hornykiewicz, O. (1978) Psychopharmacological implications of dopamine and dopamine antagonists. Neuroscience, 3, 773–783.Google Scholar
Ingvar, D. H. (1987) Evidence for frontal/prefrontal cortical dysfunction in chronic schizophrenia: the phenomenon of “hypofrontality” reconsidered In Biological Perspectives of Schizophrenia (eds H Helmchen & F. A. Henn). Chichester: Wiley.Google Scholar
Ingvar, D. H. & Franzen, G. (1974) Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatrica Scandinavica, 50, 425–436.Google Scholar
Jacob, H. & Beckmann, H. (1986) Prenatal development disturbances in the limbic allocortex in schizophrenics. Journal of Neural Transmission, 65, 303–326.Google Scholar
Kaff, B. S., Schwaber, J. S. & Driscoll, P. A. (1985) Frontal cortex projections to the amygdaloid central nucleus in the rabbit. Neuroscience, 15, 327–346.Google Scholar
Kerwin, R. W., Patel, S., Meldrum, B. S., et al (1988) Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia. Lancet, i, 583–584.Google Scholar
Kim, J. S., Kornhuber, J. J., Schmid-Burgk, W., et al (1989) Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neuroscience Letters, 20, 379–382.CrossRefGoogle Scholar
Kleinman, J. E., Iadarola, M., Govoni, S., et al (1983) Postmortem measurements of neuropeptides in human brain. Psychopharmacology Bulletin, 19, 375–377.Google Scholar
Kleinman, J. E., Casanova, M. F. & Jaskiw, G. E. (1988) The neuropathology of schizophrenia. Schizophrenia Bulletin, 14, 209–216.Google Scholar
Kovelman, J. A. & Scheibel, A. B. (1984) A neurohistological correlate of schizophrenia. Biological Psychiatry, 19, 1601–1621.Google Scholar
Lee, T., Seeman, P., Tourtellotte, W. W., et al (1978) Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains. Nature, 274, 897–900.Google Scholar
Losconczy, M. F., Song, I. S., Mohs, R. C., et al (1986) Correlates of lateral ventricle size in chronic schizophrenia. II: biological correlates. American Journal of Psychiatry, 143, 1113–1118.Google Scholar
Mackay, A. V. P., Iversen, L. L., Rossor, M., et al (1982) Increased brain dopamine and dopamine receptors in schizophrenia. Archives of General Psychiatry, 39, 991–997.Google Scholar
McKenna, P. J. (1987) Pathology, phenomenology and the dopamine hypothesis of schizophrenia. British Journal of Psychiatry, 151, 288–301.Google Scholar
Memo, M., Kleinman, J. E. & Hanbauer, I. (1983) Coupling of dopamine D1 recognition sites with adenylate cyclase in nuclei accumbens and caudatus of schizophrenia. Science, 221, 1304–1307.Google Scholar
Montgomery, S. A. & Green, M. C. D. (1988) The use of cholecystokinin in schizophrenia: a review. Psychological Medicine, 18, 593–603.Google Scholar
Morrison, F. & Poletti, C. E. (1980) Hippocampal influence on amygdala unit activity in awake squirrel monkeys. Brain Research, 192, 353–369.Google Scholar
Nishikawa, T., Takashima, M. & Toru, M. (1983) Increased (3H)kainic acid binding in the prefrontal cortex in schizophrenia. Neuroscience Letters, 40, 245–250.Google Scholar
Ounsted, C. & Lindsay, J. (1981) In: Epilepsy and Psychiatry (eds E H. Reynolds & M. R. Trimble). Edinburgh: Churchill Livingstone.Google Scholar
Owen, F., Crow, T. J., Poulter, M., et al (1978) Increased dopamine-receptor sensitivity in schizophrenia. Lancet, ii, 223–225.Google Scholar
Owen, F., & Crow, T. J., (1987) Neurotransmitters and psychosis. British Medical Bulletin, 43, 651–671.CrossRefGoogle ScholarPubMed
Pakkenberg, B. (1987) Postmortem study of chronic schizophrenic brains. British Journal of Psychiatry, 151, 744–752.CrossRefGoogle ScholarPubMed
Pickar, D., Labarca, R., Linnoila, M., et al (1984) Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science, 225, 954–957.Google Scholar
Pickar, D., Labarca, R., Doran, A. R., et al (1986) Longitudinal measurement of plasma homovanillic acid levels in schizophrenic patients. Archives of General Psychiatry, 43, 669–676.CrossRefGoogle ScholarPubMed
Potkin, S. G., Weinberger, D. R., Linnoila, M., et al (1983) Low CSF 5-hydroxyindoleacetic acid in schizophrenic patients with enlarged ventricles. American Journal of Psychiatry, 140, 21–25.Google Scholar
Pycock, C. J., Kerwin, R. W. & Carter, C. J. (1980) Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature, 286, 74–77.Google Scholar
Randrup, A. & Munkvad, I. (1965) Special antagonism of amphetamine-induced abnormal behaviour. Psychopharmacologia, 7, 416–422.Google Scholar
Reynolds, G. P. (1983) Increased concentrations and lateral asymmetry of amygdala dopamine in schizophrenia. Nature, 305, 527–529.Google Scholar
Reynolds, G. P. (1986) Amygdala dopamine asymmetry in schizophrenia: neurochemical evidence for a left temporal lobe dysfunction In Dopaminergic Systems and Their Regulation (eds G. N. Woodruff, J. A. Poat & P. J. Roberts). London: Macmillan.Google Scholar
Reynolds, G. P. (1987) Postmortem neurochemical studies in schizophrenia In Search for the Causes of Schizophrenia (eds H. Haefner, W. F. Gattaz & W. Janzarik). Heidelberg: Springer.Google Scholar
Reynolds, G. P. (1988) Postmortem neurochemistry of schizophrenia. Psychological Medicine, 18, 793–797.Google Scholar
Reynolds, G. P., Riederer, P., Jellinger, K., et al (1981) Dopamine receptors and schizophrenia: the neuroleptic drug problem. Neuropharmacology, 20, 1319–1320.Google Scholar
Reynolds, G. P., Czudek, C., Bzowej, N., et al (1987) Dopamine receptor asymmetry in schizophrenia. Lancet, i, 979.CrossRefGoogle Scholar
Reynolds, G. P., & Czudek, C., (1988) Status of the dopaminergic system in postmortem brain in schizophrenia. Psychopharmacology Bulletin, 24, 345–347.Google Scholar
Roberts, E. (1972) An hypothesis suggesting that there is a deficit in the GABA system in schizophrenia. Neuroscience Research Program Bulletin, 10, 468–481.Google Scholar
Roberts, G. W. (1989) Brain development and CCK systems in schizophrenia: a working hypothesis In Advances in Biological Psychiatry (ed.) M. P. O. Weller. London: Libbey (in press).Google Scholar
Roberts, G. W., Ferrier, I. N., Lee, Y., et al (1983) Peptides, the limbic lobe and schizophrenia. Brain Research, 288, 199–211.Google Scholar
Seeman, P., Lee, T., Chau-Wong, M., et al (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature, 261, 717–719.Google Scholar
Seeman, P., Ulpian, C., Bergeron, C., et al (1984) Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science, 225, 728–731.Google Scholar
Seeman, P., Bzowej, N. H., Guan, H. C., et al (1987) Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's and Huntington's diseases. Neuropsychopharmacology, 1, 5–15.Google Scholar
Snyder, S. H., Banerjee, S. P., Yamamura, H. T., et al (1974) Drugs, neurotransmitters and schizophrenia. Science, 184, 1243–1253.Google Scholar
Somogyi, P., Hodgson, A. J., Smith, A. D., et al (1984) Different populations of GABAergic neurons in the visual cortex and hippocampus of cat contain somatostatin- or cholecystokinin-immunoreactive material. Journal of Neuroscience, 4, 2590–2603.Google Scholar
Stanley, M., Traskman-Bendz, L. & Dorovini-Zis, K. (1985) Correlations between aminergic metabolites simultaneously obtained from human CSF and brain. Life Sciences, 37, 1279–1286.Google Scholar
Stevens, J. R. (1973) An anatomy of schizophrenia? Archives of General Psychiatry, 29, 177–189.Google Scholar
Stevens, J. R. & Livermore, A. (1978) Kindling of the mesolimbic dopamine systems. Animal model of psychosis. Neurology, 28, 36–46.Google Scholar
Thaker, G. K., Tamminga, C. A., Alphs, L. D., et al (1987) Brain γ-aminobutyric acid abnormality in tardive dyskinesia. Archives of General Psychiatry, 44, 522–529.Google Scholar
Torrey, E. F. & Peterson, M. R. (1974) Schizophrenia and the limbic system. Lancet, ii, 942–946.Google Scholar
Tyrer, P. & Mackay, A. (1986) Schizophrenia: no longer a functional psychosis. Trends in Neurosciences, 9, 537–538.Google Scholar
Van Kammen, D. P., Mann, L. S., Sternberg, D. E., et al (1983) Dopamine-β-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenic with brain atrophy. Science, 220, 974–977.Google Scholar
Van Ree, J. M., Gaffori, O. & De Wied, D. (1983) In rats the behavioural profile of CCK-8 related peptides resembles that of antipsychotic agents. European Journal of Pharmacology, 93, 63–78.Google Scholar
Waddington, J. L. (1989) Sight and insight: brain dopamine receptor occupancy by neuroleptics visualised in living schizophrenic patients by positron emission tomography. British Journal of Psychiatry, 154, 433–436.Google Scholar
Waddington, J. L. & Crow, T. J. (1988) Abnormal involuntary movements and psychosis in the pre-neuroleptic era and in unmedicated patients: implications for the concept of tardive dyskinesia In Tardive Dyskinesia: Biological Mechanisms and Clinical Aspects (eds M E. Wolf & A. D. Mosnaim). Washington, DC: American Psychiatric Press.Google Scholar
Weinberger, D. R. (1987) Implication of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry, 44, 660–669.CrossRefGoogle ScholarPubMed
Weinberger, D. R. (1988) Schizophrenia and the frontal lobe. Trends in Neurosciences, 11, 367–370.Google Scholar
Weinberger, D. R. & Berman, K. F. (1988) Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia. Schizophrenia Bulletin, 14, 157–168.Google Scholar
Wong, D. F., Wagner, H. N., Tune, L. E., et al (1986) Positron emission tomography reveals elevated D-2 dopamine receptors in drug-naive schizophrenics. Science, 234, 1558–1563.Google Scholar
Zeeberg, B. R., Gibson, R. E. & Reba, R. C. (1988) Elevated D2 dopamine receptors in drug naive schizophrenics. Science, 239, 789–790.Google Scholar
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