Abstract
In a recent study, we demonstrated that cytochrome-c oxidase (COX), an indicator of neuronal activity, is increased in several brain regions from chronic, medicated schizophrenics. In the present study, to address the functional significance of those findings, we have measured COX activity in a group of schizophrenics in whom antemortem geriatric measures of motor, intellectual, and emotional impairment had been assessed. COX activity in the putamen was strongly negatively correlated with emotional (r = −.76; p < .005) and intellectual impairment (r = −0.76; p < .005), but not with motor impairment (r = 0.01). No significant correlations could be found in the frontal cortex, thalamus, caudate nucleus, globus pallidus, mesencephalon, or nucleus accumbens. Dopamine D2 receptor density in the putamen, measured with [3H]raclopride, was elevated in schizophrenics as compared to controls, as were Kd values. In contrast to COX activity, D2 receptor binding was moderately, but significantly positively correlated with intellectual impairment (r = 0.64; p < .05) but not with motor impairment. Results expose a unique anomaly in the effects of neuroleptics in terms of increasing neuronal signaling in the putamen, which may underlie a reversal of cognitive deficits in schizophrenics, while at the same time, elevating D2 receptor density that seems to be detrimental.
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References
Adolfsson R, Gottfries CG, Nystrom L, Winblad B . (1981): Prevalence of dementia disorders in institutionalized Swedish old people. The work load imposed by caring for these patients. Acta Psychiat Scand 63: 225–244
Andreasen NC, O′Leary DS, Cizadlo T, Arndt S, Rezai K, Ponto LL, Watkins GL, Hichwa RD . (1996): Schizophrenia and cognitive dysmetria: A positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Nat Acad Sci USA 93: 9985–9990
Andreasen NC, O′Leary DS, Flaum M, Nopoulos P, Watkins GL, Boles Ponto LL, Hichwa RD . (1997): Hypofrontality in schizophrenia: Distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349: 1730–1734
Andreasen NC . (1997): Linking mind and brain in the study of mental illnesses: A project for a scientific psychopathology. Science 275: 1586–1593
Brown LL, Schneider JS, Lidsky TI . (1997): Sensory and cognitive functions of the basal ganglia. Curr Opin Neurobiol 7: 157–163
Buchsbaum MS, Haier RJ, Potkin SG, Nuechterlein K, Bracha HS, Katz M, Lohr J, Wu J, Lottenberg S, Jerabek PA, Trenary M, Tafalla R, Reynolds C, Bunney WE . (1992): Fontostriatal disorder of cerbral metabolism in never-medicated schizophrenics. Arch Gen Psychiat 49: 935–942
Buchsbaum MS, Ingvar DH, Kessler R, Waters RN, Cappelletti J, van Kammen DP, King AC, Johnson JL, Manning RG, Flynn RW, Mann LS, Bunney WE Jr, Sokoloff L . (1982): Cerebral glucography with positron tomography. Use in normal subjects and in patients with schizophrenia. Arch Gen Psychiat 39: 251–259
Burt DR, Creese I, Snyder SH . (1977): Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain. Science 196: 326–328
Carlsson M, Carlsson A . (1990): Interactions between glutamatergic and monoaminergic systems within the basal ganglia—Implications for schizophrenia and Parkinson's disease. Trends Neurosci 13: 272–276
Carlsson A, Hansson LO, Waters N, Carlsson ML . (1997): Neurotransmitter aberrations in schizophrenia: New perspectives and therapeutic implications. Life Sci 61: 75–94
Casey DE . (1995): Motor and mental aspects of extrapyramidal syndromes. Int Clin Psychopharmacol 10: 105–114
Cavelier L, Jazin EE, Eriksson I, Prince J, Bave U, Oreland L, Gyllensten U . (1995): Decreased cytochrome-c oxidase activity and lack of age-related accumulation of mitochondrial DNA deletions in the brains of schizophrenics. Genomics 29: 217–224
DeLisi LE, Holcomb HH, Cohen RM, Pickar D, Carpenter W, Morihisa JM, King AC, Kessler R, Buchsbaum MS . (1985): Positron emission tomography in schizophrenic patients with and without neuroleptic medication. J Cereb Blood Flow Metab 5: 201–206
Downs TR, Wilfinger WW . (1983): Fluorometric quantification of DNA in cells and tissue. Anal Biochem 131: 538–547
Eastwood SL, Burnet PW, Harrison PJ . (1994): Striatal synaptophysin expression and haloperidol-induced synaptic plasticity. NeuroReport 5: 677–680
Farde L, Gustavsson JP, Jonsson E . (1997): D2 dopamine receptors and personality traits. Nature 385: 590
Hevner RF, Duff RS, Wong-Riley MTT . (1992): Coordination of ATP production and consumption in brain: Parallel regulation of cytochrome oxidase and Na+,K+-ATPase. Neurosci Lett 138: 188–192
Hindmarch I . (1994): Instrumental assessment of psychomotor functions and the effects of psychotropic drugs. Acta Psychiat Scand Suppl 380: 49–52
Holcomb HH, Cascella NG, Thaker GK, Medoff DR, Dannals RF, Tamminga CA . (1996): Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol. Am J Psychiat 153: 41–49
Humphries C, Mortimer A, Hirsch S, de Belleroche J . (1996): NMDA receptor mRNA correlation with antemortem cognitive impairment in schizophrenia. NeuroReport 7: 2051–2055
King DJ . (1990): The effect of neuroleptics on cognitive and psychomotor function. Br J Psychiat 157: 799–811
Lepiku M, Rinken A, Järv J, Fuxe K . (1996): Kinetic evidence for isomerization of the dopamine receptor—raclopride complex. Neurochem Int 28: 591–595
Levy R, Friedman HR, Davachi L, Goldman-Rakic PS . (1997): Differential activation of the caudate nucleus in primates performing spatial and nonspatial working memory tasks. J Neurosci 17: 3870–3882
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ . (1951): Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275
Mackay AV, Iversen LL, Rossor M, Spokes E, Bird E, Arregui A, Creese I, Synder SH . (1982): Increased brain dopamine and dopamine receptors in schizophrenia. Arch Gen Psychiat 39: 991–997
Markwell MAC, Maas SM, Biebar LL, Tolbert NE . (1978): A modification of the Lowry procedure to simplify protein determination in membrane and in protein samples. Anal Biochem 87: 206–211
Nordahl TE, Kusubov N, Carter C, Salamat S, Cummings AM, O′Shora-Celaya L, Eberling J, Robertson L, Huesman RH, Jagust W, Budinger TF . (1996): Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600. Neuropsychopharmacology 15: 541–554
Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M . (1997): Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 385 6617: 634–636
Prince JA, Blennow K, Gottfries CG, Karlsson I, Oreland L . (1999): Mitochondrial function is differentially altered in the basal ganglia of chronic schizophrenics. Neuropsychopharmacology 21: 372–379
Prince JA, Yassin MS, Oreland L . (1997a): Neuroleptic-induced mitochondrial enzyme alterations in the rat brain. J Pharm Exp Ther 280: 261–267
Prince JA, Yassin MS, Oreland L . (1998): A histochemical demonstration of altered cytochrome oxidase acitivty in the rat brain by neuroleptics. Eur Neuropsychopharmacol 8: 1–6
Prince JA, Yassin M, Oreland L . (1997b): Normalization of cytochrome-c oxidase activity in the rat brain by neuroleptics after chronic treatment with PCP or methamphetamine. Neuropharmacology 36: 1665–1678
Rago R, Mitchen J, Wilding G . (1990): DNA fluorometric assay in 96-well tissue culture plates using hoechst 33258 after cell lysis by freezing in distilled water. Anal Biochem 191: 31–34
Sabri O, Erkwoh R, Schreckenberger M, Owega A, Sass H, Buell U . (1997): Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics. Lancet 349: 1735–1739
Saykin AJ, Gur RC, Gur RE, Mozley PD, Mozley LH, Resnick SM, Kester DB, Stafiniak P . (1991): Neuropsychological function in schizophrenia. Selective impairment in memory and learning. Arch Gen Psychiat 48: 618–624
Shenton ME, Kikinis R, Jolesz FA, Pollak SD, LeMay M, Wible CG, Hokama H, Martin J, Metcalf D, Coleman M, McCarley RW . (1992): Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. N Engl J Med 327: 604–612
Shihabuddin L, Buchsbaum MS, Hazlett EA, Haznedar MM, Harvey PD, Newman A, Schnur DB, Spiegel-Cohen J, Wei T, Machac J, Knesaurek K, Vallabhajosula S, Biren MA, Ciaravolo TM, Luu-Hsia C . (1998): Dorsal striatal size, shape, and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task. Arch Gen Psychiat 55: 235–243
Siegel BV, Buchsbaum MS, Bunney WE Jr, Gottschalk LA, Haier RJ, Lohr JB, Lottenberg S, Najafi A, Nuechterlein KH, Potkin SG . (1993): Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients. Am J Psychiat 150: 1325–1336
Singer VL, Jones LJ, Yue ST, Haugland RP . (1997): Characterization of PicoGreen reagent and development of a fluorescence-based solution assay for double-stranded DNA quantitation. Anal Biochem 249: 228–238
Smith AD, Bolam JP . (1990): The neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurones. Trends Neurosci 13: 259–265
Stratta P, Mancini F, Mattei P, Daneluzzo E, Casacchia M, Rossi A . (1997): Association between striatal reduction and poor Wisconsin Card Sorting Test performance in patients with schizophrenia. Biol Psychiat 42: 816–820
Weinberger DR, Gallhofer B . (1997): Cognitive function in schizophrenia. Int Clin Psychopharmacol 12: S29–S36
Wong-Riley M . (1979): Changes in the visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry. Brain Res 171: 11–28
Wong-Riley M . (1989): Cytochrome oxidase: An endogenous metabolic marker for neuronal activity. TINS 12: 94–101
Wong-Riley M, Carrol EW . (1984): Effect of impulse blockage on cytochrome oxidase activity in monkey visual system. Nature 307: 262–264
Yonetani T, Ray G . (1965): Studies on cytochrome oxidase. J Biol Chem 240: 3392–3399
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This work was supported by grants from the Swedish Medical Research Council (Project 4145), The Foundation for “Gamla Tjänarinnor,” and The Foundation for Psychiatric and Neurological Research.
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Prince, J., Harro, J., Blennow, K. et al. Putamen Mitochondrial Energy Metabolism Is Highly Correlated to Emotional and Intellectual Impairment in Schizophrenics. Neuropsychopharmacol 22, 284–292 (2000). https://doi.org/10.1016/S0893-133X(99)00111-6
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DOI: https://doi.org/10.1016/S0893-133X(99)00111-6
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