The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia

Alessandro Bertolino, Michael B. Knable, Richard C. Saunders, Joseph H. Callicott, Bhaskar Kolachana, Venkata S. Mattay, Jocelyne Bachevalier, Joseph A. Frank, Michael Egan, Daniel R. Weinberger

Research output: Contribution to journalArticle

Abstract

Background: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development. Methods: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. Results: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D2 receptor availability in the striatum (n = 14, rho = -.64, p <.01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p <.05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. Conclusions: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.

Original languageEnglish
Pages (from-to)660-667
Number of pages8
JournalBiological Psychiatry
Volume45
Issue number6
DOIs
Publication statusPublished - Mar 15 1999

Keywords

  • Dopamine
  • Dorsolateral prefrontal cortex
  • Microdialysis
  • N-acetylaspartate
  • Radio-receptor imaging
  • Striatum

ASJC Scopus subject areas

  • Biological Psychiatry

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    Bertolino, A., Knable, M. B., Saunders, R. C., Callicott, J. H., Kolachana, B., Mattay, V. S., Bachevalier, J., Frank, J. A., Egan, M., & Weinberger, D. R. (1999). The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia. Biological Psychiatry, 45(6), 660-667. https://doi.org/10.1016/S0006-3223(98)00380-1