Abstract
Schizophrenia has been linked to abnormal dopamine function, recently to excessive amphetamine-induced release of striatal dopamine, and also to pathology of prefrontal cortical neurons. It has been hypothesized that prefrontal pathology is a primary condition that leads to dopamine dysregulation. We evaluated in vivo the relationship between neuronal integrity in dorsolateral prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations measured with proton magnetic resonance spectroscopic imaging, and amphetamine-induced release of striatal dopamine, assessed with 11C-raclopride Positron Emission Tomography (PET) in patients with schizophrenia and in healthy subjects. In the patients, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C-raclopride after amphetamine infusions (rho = − 0.76, p < .02). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, Van Dyck CH, Charney DS, Innis RB, Laruelle M . (1998): Increased striatal dopamine transmission in schizophrenia: Confirmation in a second cohort. Am J Psychiatry 155: 761–767
Akbarian S, Sucher NJ, Bradley D, Taffazzoli A, Trinh D, Hetrick WP, Potkin SG, Sandman CA, Bunney WE, Jones EG . (1996): Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J Neurosci 16: 19–30
Bates TE, Stranward M, Keelan J, Davey GP, Munro PMG, Clark JB . (1996): Inhibition of N-acetylaspartate production: Implications for 1H MRS studies. Neuroreport 7: 1397–1400
Bertolino A, Callicott JH, Elman I, Mattay VS, Tedeschi G, Frank JA, Breier A, Weinberger DR . (1998a): Regionally specific neuronal pathology in untreated patients with schizophrenia: A proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 43: 641–648
Bertolino A, Callicott JH, Nawroz S, Mattay VS, Duyn JH, Tedeschi G, Frank JA, Weinberger DR . (1998b): Reproducibility of proton magnetic resonance spectroscopic imaging in patients with schizophrenia. Neuropsychopharmacology 18: 1–9
Bertolino A, Esposito G, Callicott JH, Mattay VS, vVan Horn JD, Frank JA, Berman KF, Weinberger DR . (1997): 1H-MRSI correlates with rCBF activation during working memory in patients with schizophrenia. Neuroimage 5: 281
Bertolino A, Knable MB, Saunders RC, Callicott JH, Kolachana BS, Mattay VS, Bachevalier J, Egan MF, Frank JA, Weinberger DR . (1999): The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia. Biol Psychiatry 45: 660–667
Bertolino A, Nawroz S, Mattay VS, Duyn JH, Moonen CTW, Barnett AS, Frank JA, Tedeschi G, Weinberger DR . (1996): A specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 153: 1554–1563
Braun AR, Jaskiw GE, Vladar K, Sexton RH, Kolachana BS, Weinberger DR . (1993): Effects of ibotenic acid lesion of the medial prefrontal cortex on dopamine agonist-related behaviors in the rat. Pharm Biochem Behav 46: 51–60
Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, De Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D . (1997): Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94: 2569–2574
Buckley PF, Moore C, Long H, Larkin C, Thompson P, Mulvany F, Redmond O, Stack JP, Ennis JT, Waddington JL . (1994): 1H Magnetic resonance spectroscopy of the left temporal and frontal lobes in schizophrenia: Clinical neurodevelopmental and cognitive correlates. Biol Psychiatry 36: 792–800
Callicott JH, Eegan MF, Bertolino A, Mattay VS, Langheim FJP, Frank JA, Weinberger DR . (1998): Hippocampal N-acetylaspartate in unaffected siblings of patients with schizophrenia: A possible intermediate phenotype. Biol Psychiatry 44: 941–950
Carlsson A . (1988): The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1: 179–186
Cendes F, Andermann F, Dubeau F, Matthews PM, Arnold DL . (1997): Normalization of neuronal metabolic dysfunction after surgery for temporal lobe epilepsy. Evidence from proton MR spectroscopic imaging. Neurology 49: 1525–1533
Clark JB . (1998): N-acetyl aspartate: A marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20: 271–276
Davis KL, Kahn RS, Ko G, Davidson M . (1991): Dopamine in schizophrenia: A review and reconceptualization Am J Psychiatry 148: 1474–1486
Deicken RF, Zhou L, Schuff N, Fein G, Weiner MW . (1998): Hippocampal neuronal dysfunction in schizophrenia as measured by proton magnetic resonance spectroscopy. Biol Psychiatry 43: 483–488
Del Arco A, Martinez R, Mora F . (1998): Amphetamine increases extracellular concentrations of glutamate in the prefrontal cortex of the awake rat: A microdialysis study. Neurochem Res 23: 1153–1158
De Stefano N, Matthews P, Antel JP, Preul M, Francis G, Arnold DL . (1995): Chemical pathology of acute demyelinating lesions and its correlations with disability. Ann Neurol 38: 901–909
Deutch AY . (1992): 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
Divac I, Kosmal A, Bjorklund A, Lindvall O . (1978): Subcortical projections to the prefrontal cortex in the rat as revealed by the horseradish peroxidase technique. Neuroscience 3: 785–796
Duyn JH, Gillen J, Sobering G, van Zijl PC, Moonen CTW . (1993): Multisection proton MR spectroscopic imaging of the brain. Radiology 188: 277–282
Eastwood SL, McDonald B, Burnet PW, Beckwith JP, Kerwin RW, Harrison PJ . (1995): Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. Mol Brain Res 29: 211–223
Flores G, Wood GK, Liang JJ, Quirion R, Srivastava LK . (1996): Enhanced amphetamine sensitivity and increased expression of dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex. J Neurosci 16: 7366–7375
Goldman-Rakic PS . (1987): Handbook of Physiology: The Nervous System. Bethesda, MD, American Physiological Society, pp 373–417
Grace AA . (1991): Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia. Neuroscience 41: 1–24
Hietala J, Syvalahti E, Vuorio K . (1994): Striatal dopamine D2 receptor binding characteristics in neuroleptic naive schizophrenics studied with positron emission tomography. Arch Gen Psychiatry 51: 116–123
Jaskiw GE, Karoum FK, Weinberger DR . (1990): 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
Knable MB, Egan MF, Heinz A, Gorey J, Lee KS, Coppola R, Weinberger DR . (1997): Evidence for a relationship between altered dopaminergic function and negative symptoms in drug-free schizophrenic patients: An I-123 IBZM-SPECT study. Br J Psychiatry 171: 574–577
Kornhuber J, Riederer P, Reynolds GP, Beckmann H, Jellinger K, Gabriel E . (1989): 3H-spiperone binding sites in post-mortem brains from schizophrenic patients: Relationship to neuroleptic drug treatment, abnormal movements, and positive symptoms. J Neural Transm 75: 1–10
Laruelle M, Abi-Dargham A, van-Dyck CH, Gil R, D'Souza CD, Erdos J, McKCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB . (1996): Single-photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci 93: 9235–9240
Lee T, Seeman P, Toutellotte WW, Farley IJ, Hornykiewicz O . (1978): Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains. Nature 274: 897–900
Maier M, Ron MA, Barker GJ, Tofts PS . (1995): Proton magnetic resonance spectroscopy: An in vivo method of estimating hippocampal neuronal depletion in schizophrenia. Psychol Med 25: 1201–1209
Moffett JR, Namboodiri MA . (1995): Differential distribution of N-acetylaspartylglutamate and N-acetylaspartate immunoreactivities in rat forebrain. J Neurocytol 24: 409–433
Moghaddam B, Adams BW . (1998): Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281: 1349–1352
Murase S, Grenhoff J, Chouvet G, Gonon FG, Svensson TH . (1993): Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo. Neurosci Lett 157: 53–56
Najim IM, Wang Y, Shedid D, Luders HO, Ng TC, Comair YG . (1998): MRS metabolic markers of seizures and seizure-induced neuronal damage. Epilepsia 39: 244–250
Nasrallah HA, Skinner TE, Schmalbrock P, Robitaille PM . (1994): Proton magnetic resonance spectroscopy of the hippocampal formation in schizophrenia: A pilot study. Br J Psychiatry 165: 481–485
Pettigrew JW, Keshavan MS, Panchalingam K, Strychor S, Kapla DB, Tretta MG, Allen M . (1991): Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 48 (6): 563–568
Renshaw PF, Yurgelun-Todd DA, Tohen MSG, Cohen BM . (1995): Temporal lobe proton magnetic resonance spectroscopy of patients with first-episode psychosis. Am J Psychiatry 152: 444–446
Roberts AC, De Salvia MA, Wilkinson LS, Collins P, Muir JL, Everitt BJ, Robbins TW . (1994): 6-hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: Possible interactions with subcortical dopamine. J Neurosci 14: 2531–2544
Rubin Y, LaPlaca MC, Smith DH, Thibault LE, Lenkinski RE . (1995): The effect of N-acetyl-aspartate on the intracellular calcium concentration in NTera2-neurons. Neurosci Lett 198: 209–212
Saunders RC, Kolachana B, Bachevalier J, Weinberger DR . (1998): Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine. Nature 393: 169–171
Selemon LD, Rajkowska G, Goldman-Rakic PS . (1995): Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52: 805–818
Shim SS, Bunney BS, Shi WX . (1996): Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons. Neuropsychopharmacology 15: 437–441
Stanley JA, Williamson PC, Drost DJ, Rylett RJ, Carr TJ, Malla A, Thompson RT . (1996): An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients. Schizophr Bull 22: 597–609
Svensson TH, Tung CS . (1989): Local cooling of prefrontal cortex induces pacemaker-like firing of dopamine neurons in rat ventral tegmental area in vivo. Acta Physiol Scand 136: 135–136
Urenjak J, Williams SR, Gadian DG, Noble M . (1993): Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 13: 981–989
Weinberger DR . (1987): Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44: 660–669
Weinberger DR . (1999): Cell Biology of the Hippocampal Formation in Schizophrenia. Biol Psychiatry 45: 395–402
Weinberger DR, Berman KF, Zec RF . (1986): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiatry 43: 114–125
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bertolino, A., Breier, A., Callicott, J. et al. The Relationship between Dorsolateral Prefrontal Neuronal N-Acetylaspartate and Evoked Release of Striatal Dopamine in Schizophrenia. Neuropsychopharmacol 22, 125–132 (2000). https://doi.org/10.1016/S0893-133X(99)00096-2
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(99)00096-2
Keywords
This article is cited by
-
Metabolite differences in the medial prefrontal cortex in schizophrenia patients with and without persistent auditory verbal hallucinations: a 1H MRS study
Translational Psychiatry (2022)
-
Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia
Molecular Psychiatry (2022)
-
The relationship between grey matter volume and striatal dopamine function in psychosis: a multimodal 18F-DOPA PET and voxel-based morphometry study
Molecular Psychiatry (2021)
-
Sex differences in amphetamine-induced dopamine release in the dorsolateral prefrontal cortex of tobacco smokers
Neuropsychopharmacology (2019)
-
Highly selective sensing of dopamine using carbon nanotube ink doped with anionic surfactant modified disposable paper electrode
Journal of Solid State Electrochemistry (2017)
