Tolcapone Improves Cognition and Cortical Information Processing in Normal Human Subjects

  title={Tolcapone Improves Cognition and Cortical Information Processing in Normal Human Subjects},
  author={Jose Apud and Venkata S. Mattay and Jingshan Chen and Bhaskar S. Kolachana and Joseph H. Callicott and Roberta Rasetti and Guilna Alce and Jennifer Iudicello and Natkai Akbar and Michael Egan and Terry E. Goldberg and Daniel R. Weinberger},
Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe… 
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Basic evidence of an inverted-“U” functional-response curve to increasing dopamine signaling in the prefrontal cortex is extended and individuals with the met/met catechol O-methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine.
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The data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
Catechol-O-Methyltransferase Inhibition Improves Set-Shifting Performance and Elevates Stimulated Dopamine Release in the Rat Prefrontal Cortex
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Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow
Findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function, and age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.
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Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia
Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val108/158 Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism.