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Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype

Abstract

Using multimodal neuroimaging in humans, we demonstrate specific interactions between prefrontal activity and midbrain dopaminergic synthesis. A common V(108/158)M substitution in the gene for catecholamine-O-methyltransferase (COMT), an important enzyme regulating prefrontal dopamine turnover, predicted reduced dopamine synthesis in midbrain and qualitatively affected the interaction with prefrontal cortex. These data implicate a dopaminergic tuning mechanism in prefrontal cortex and suggest a systems-level mechanism for cognitive and neuropsychiatric associations with COMT.

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Figure 1: Midbrain dopamine and relationship with prefrontal rCBF.
Figure 2: Interactions of cortical rCBF with midbrain dopamine.

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Acknowledgements

We thank D. Sarpal, P. Koch and A. Bonner-Jackson for research assistance, M. Akil and V. Mattay for helpful discussion of this manuscript vis à vis their own results, A. Grace for helpful comments on the interpretation of the data, T. Goldberg for neuropsychological testing and R. Carson for expertise in PET kinetic modeling.

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Correspondence to Andreas Meyer-Lindenberg.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Relationship between dopaminergic stimulation and prefrontal cortex activity, drawn schematically after Goldman-Rakic et al. and Mattay et al. In the latter study, the differential effect of an acute increase in dopaminergic tone induced by amphetamine was used to probe the position on the u-shaped curve in the setting of acute pharmacological modulation, which led to improved function and prefrontal efficiency in val-allele carriers, but deteriorating function in met-homozygotes. (JPG 48 kb)

Supplementary Fig. 2

Task-related activations and deactivations. Effect of task - significant activations (red) and deactivations (blue), comparing the working memory (2-back) condition with its sensorimotor control (0-back). Highlighted voxels are significant at theP0.05 corrected level (see Supplementary Tables 1 and 2). (JPG 99 kb)

Supplementary Fig. 3

Hypothetical fit of data to “inverted-u” response curve. “Inverted-u” shaped relationship between observed left DLPFC 0-back rCBF and dopamine synthesis rate, hypothetically assuming that a given rate of midbrain dopamine neuronal activity and dopamine synthesis (Ki) will result in twice as much prefrontal dopamine in met-homozygotes (see discussion in Chen et al. 2004); to reflect this, Kis were doubled for met-homozygotes. Second-order polynomial fit curve shown. Datapoints for val-carriers shown as filled circles, met-homozygotes as empty circles. (JPG 33 kb)

Supplementary Table 1

Further subject information and ROI measurements, by genotype. (PDF 48 kb)

Supplementary Table 2

Working-memory task related activations. (PDF 42 kb)

Supplementary Table 3

Working-memory task related deactivations. (PDF 42 kb)

Supplementary Table 4

Correlations of PFC rCBF with midbrain F-DOPA Ki. (PDF 45 kb)

Supplementary Methods (PDF 56 kb)

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Meyer-Lindenberg, A., Kohn, P., Kolachana, B. et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci 8, 594–596 (2005). https://doi.org/10.1038/nn1438

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