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The Journal of Neuroscience, September 19, 2007, 27(38):10196-10209; doi:10.1523/JNEUROSCI.0665-07.2007

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Behavioral/Systems/Cognitive
Site-Specific Role of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsal Striatum

Leonid Yavich,^1,2 Markus M. Forsberg,² Maria Karayiorgou,³ Joseph A. Gogos,⁴ and Pekka T. Männistö^2,5

¹In Vivo Voltammetry Contract Research Laboratory and ²Department of Pharmacology and Toxicology, University of Kuopio, FIN-70211 Kuopio, Finland, ³Laboratory of Human Neurogenetics, The Rockefeller University, New York, New York 10021, ⁴Department of Physiology and Cellular Biophysics and Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, New York 10032, and ⁵Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, FIN-00014, Helsinki, Finland

Correspondence should be addressed to Dr. Leonid Yavich, Department of Pharmacology and Toxicology, University of Kuopio, FIN-70211 Kuopio, Finland. Email: leonid.yavich{at}uku.fi

Accumulating evidence from clinical and preclinical studies shows that catechol-O-methyltransferase (COMT) plays a significant role in dopamine metabolism in the prefrontal cortex, but not in the striatum. However, to what extent dopamine overflow in the prefrontal cortex and striatum is controlled by enzymatic degradation versus reuptake is unknown. We used COMT deficient mice to investigate the role of COMT in these two brain regions with in vivo voltammetry. A real-time analysis of evoked dopamine overflow showed that removal of dopamine was twofold slower in the prefrontal cortex of mice lacking COMT than in wild-type mice, indicating that half of the dopamine decline in this brain region results from COMT-mediated enzymatic degradation. Lack of COMT did not influence dopamine overflow/decline in the dorsal striatum. COMT-deficient mice demonstrated a small (20–25%) but consistent increase in evoked dopamine release in the prefrontal cortex, but not in the dorsal striatum. Cocaine affected equally dopaminergic neurotransmission in the prefrontal cortex in both genotypes by prolonging 3–4 times dopamine elimination from extracellular space. Paradoxically, this happened without increase of the peak levels of evoked dopamine release. The present findings represent the first demonstration of the significant contribution of COMT in modulating the dynamics of dopamine overflow in the prefrontal cortex and underscore the therapeutic potential of manipulating COMT activity to alter dopaminergic neurotransmission in the prefrontal cortex.

Key words: prefrontal cortex; caudate nucleus; COMT; cocaine; in vivo voltammetry; knock-out mice

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Received Feb. 14, 2007; revised Aug. 12, 2007; accepted Aug. 12, 2007.

Correspondence should be addressed to Dr. Leonid Yavich, Department of Pharmacology and Toxicology, University of Kuopio, FIN-70211 Kuopio, Finland. Email: leonid.yavich{at}uku.fi

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