Abstract
Both dopaminergic neurotransmission and prefrontal cortex (PFC) function are known to be abnormal in schizophrenia. To test the hypothesis that these phenomena are related, we measured presynaptic dopaminergic function simultaneously with regional cerebral blood flow during the Wisconsin Card Sorting Test (WCST) and a control task in unmedicated schizophrenic subjects and matched controls. We show that the dopaminergic uptake constant Ki in the striatum was significantly higher for patients than for controls. Patients had significantly less WCST-related activation in PFC. The two parameters were strongly linked in patients, but not controls. The tight within-patient coupling of these values, with decreased PFC activation predicting exaggerated striatal 6-fluorodopa uptake, supports the hypothesis that prefrontal cortex dysfunction may lead to dopaminergic transmission abnormalities.
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References
Bennett, M. R. Monoaminergic synapses and schizophrenia: 45 years of neuroleptics. J. Psychopharmacol. 12, 289–304 (1998).
Kraepelin, E., Barclay, R. M. & Robertson, G. M. Dementia Præcox and Paraphrenia (E. & S. Livingstone, Edinburgh, 1919).
Lewis, D. A. & Anderson, S. A. The functional architecture of the prefrontal cortex and schizophrenia. Psychol. Med. 25, 887–894 (1995).
Laruelle, M. & Abi-Dargham, A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J. Psychopharmacol. 13, 358–371 (1999).
Jaskiw, G. E., Karoum, F. K. & Weinberger, D. R. Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex. Brain. Res. 534, 321–323 (1990).
Pycock, C. J., Kerwin, R. W. & Carter, C. J. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature 286, 74–76 (1980).
Weinberger, D. R. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44, 660–669 (1987).
Weinberger, D. R., Berman, K. F. & Illowsky, B. P. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch. Gen. Psychiatry 45, 609–615 (1988).
Grace, A. A. Cortical regulation of subcortical dopamine systems and its possible relevance to schizophrenia. J. Neural Transm. Gen. Sect. 91, 111–134 (1993).
Deutch, A. Y. The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia. J. Neural Transm. Suppl. 36, 61–89 (1992).
Weinberger, D. R., Berman, K. F. & Zec, R. F. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch. Gen. Psychiatry 43, 114–124 (1986).
Weinberger, D. R. & Berman, K. F. Prefrontal function in schizophrenia: confounds and controversies. Phil. Trans. R. Soc. Lond. B Biol. Sci. 351, 1495–1503 (1996).
Hietala, J. et al. Depressive symptoms and presynaptic dopamine function in neuroleptic- naive schizophrenia. Schizophr. Res. 35, 41–50 (1999).
Hietala, J. et al. Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 346, 1130–1131 (1995).
Lindstrom, L. H. et al. Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by l-(β-11C) DOPA and PET. Biol. Psychiatry 46, 681–688 (1999).
Reith, J. et al. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc. Natl. Acad. Sci. USA 91, 11651–11654 (1994).
Dao-Castellana, M. H. et al. Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophr. Res. 23, 167–174 (1997).
Elkashef, A. M. et al. 6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography. Psychiatry Res. 100, 1–11 (2000).
Cumming, P., Kuwabara, H., Ase, A. & Gjedde, A. Regulation of DOPA decarboxylase activity in brain of living rat. J. Neurochem. 65, 1381–1390 (1995).
Gjedde, A. et al. Dopa decarboxylase activity of the living human brain. Proc. Natl. Acad. Sci. USA 88, 2721–2725 (1991).
Abi-Dargham, A. et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am. J. Psychiatry 155, 761–767 (1998).
Wong, D. F. et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234, 1558–1563 (1986).
Abi-Dargham, A. et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc. Natl. Acad. Sci. USA 97, 8104–8109 (2000).
Bertolino, A. et al. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology 22, 125–132 (2000).
Jackson, M. E., Frost, A. S. & Moghaddam, B. Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens. J. Neurochem. 78, 920–923 (2001).
Murase, S., Grenhoff, J., Chouvet, G., Gonon, F. G. & Svensson, T. H. Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo. Neurosci. Lett. 157, 53–56 (1993).
Christie, M. J., Bridge, S., James, L. B. & Beart, P. M. Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area. Brain Res. 333, 169–172 (1985).
Kegeles, L. S. et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol. Psychiatry 48, 627–640 (2000).
Carr, D. B. & Sesack, S. R. Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J. Neurosci. 20, 3864–3873 (2000).
Carlsson, A. et al. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu. Rev. Pharmacol. Toxicol. 41, 237–260 (2001).
Saunders, R. C., Kolachana, B. S., Bachevalier, J. & Weinberger, D. R. Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine. Nature 393, 169–171 (1998).
Swerdlow, N. R. & Geyer, M. A. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr. Bull. 24, 285–301 (1998).
Grace, A. A. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41, 1–24 (1991).
Daniel, D. G. et al. The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J. Neurosci. 11, 1907–1917 (1991).
Okubo, Y. et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 385, 634–636 (1997).
Napier, T. C. & Chrobak, J. J. Evaluations of ventral pallidal dopamine receptor activation in behaving rats. Neuroreport 3, 609–611 (1992).
Muller, U., von Cramon, D. Y. & Pollmann, S. D1- versus D2-receptor modulation of visuospatial working memory in humans. J. Neurosci. 18, 2720–2728 (1998).
Goldman-Rakic, P. S. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol. Psychiatry 46, 650–661 (1999).
Weinberger, D. R. & Lipska, B. K. Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: a search for common ground. Schizophr. Res. 16, 87–110 (1995).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-III-R (American Psychiatric Association, Washington, DC, 1987).
Miletich, R. S. et al. 6-[18F]fluoro-L-dihydroxyphenylalanine metabolism and positron emission tomography after catechol-O-methyltransferase inhibition in normal and hemiparkinsonian monkeys. Brain Res. 626, 1–13 (1993).
Berman, K. F. et al. Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: a positron emission tomography study. Neuropsychologia 33, 1027–1046 (1995).
Woods, R. P., Mazziotta, J. C. & Cherry, S. R. MRI-PET registration with automated algorithm. J. Comput. Assist. Tomogr. 17, 536–546 (1993).
Talairach, J. & Tournoux, P. Co-planar Stereotaxic Atlas of the Human Brain (Thieme, Stuttgart New York, 1988).
Brooks, D. J. et al. Differing patterns of striatal 18F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Ann. Neurol. 28, 547–555 (1990).
Patlak, C. S., Blasberg, R. G. & Fenstermacher, J. D. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J. Cereb. Blood Flow Metab. 3, 1–7 (1983).
Acknowledgements
We would like to acknowledge the support of the staff of the PET Department, Clinical Center, NIH, in the execution of this study and the help of Timothy Ellmore, in data analysis.
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Meyer-Lindenberg, A., Miletich, R., Kohn, P. et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5, 267–271 (2002). https://doi.org/10.1038/nn804
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DOI: https://doi.org/10.1038/nn804
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