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Randomized Controlled Trial
. 2013 Dec 15;133(3):852-6.
doi: 10.1016/j.drugalcdep.2013.09.003. Epub 2013 Sep 14.

Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study

Rebecca L Ashare  1 , E Paul Wileyto, Kosha Ruparel, Patricia M Goelz, Ryan D Hopson, Jeffrey N Valdez, Ruben C Gur, James Loughead, Caryn Lerman
Affiliations
Randomized Controlled Trial

Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study

Rebecca L Ashare et al. Drug Alcohol Depend. .

Abstract

Background: Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers.

Methods: In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24h of abstinence. Smokers were genotyped prospectively for the COMT val(158)met polymorphism for exploratory analysis.

Results: Compared to placebo, tolcapone modestly improved accuracy (p=0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p=0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo.

Conclusions: Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.

Keywords: COMT; Nicotine; Smoking; Tolcapone; Working memory; fMRI.

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Conflict of interest statement

Conflict of interest

Dr. Lerman has served as a consultant to Pfizer on pharmacogenetic testing for smoking cessation treatment and has received research funding from and consulted for AstraZeneca, Targacept, Pfizer, and GlaxoSmithKline, for work unrelated to this manuscript. No other authors have any potential conflict of interests to declare.

References

    1. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF, Goldberg TE, Weinberger DR. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007;32:1011–1020. - PubMed
    1. Arnsten AFT. Stress signalling pathways that impair prefrontal cortex structure and function. Nat. Rev. Neurosci. 2009;10:410–422. - PMC - PubMed
    1. Barnett JH, Scoriels L, Munafo MR. Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol. Psychiatry. 2008;64:137–144. - PubMed
    1. Chein JM, Schneider W. Neuroimaging studies of practice-related change: fMRI and meta-analytic evidence of a domain-general control network for learning. Cogn. Brain Res. 2005;25:607–623. - PubMed
    1. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet. 2004;75:807–821. - PMC - PubMed

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