1. ¹Departments of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine and Psychology, UCLA Neuropsychiatric Institute, University of California at Los Angeles, Los Angeles, CA, USA
2. ²Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
3. ³New York University School of Medicine, New York, NY, USA
4. ⁴Albert Einstein College of Medicine, Bronx, NY, USA
5. ⁵Departments of Neuroscience, Psychiatry, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: Dr RM Bilder, Departments of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine and Psychology, UCLA Neuropsychiatric Institute C8-849, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA. Tel: +1 310 825 9474; Fax: +1 310 825 2850; E-mail: rbilder@mednet.ucla.edu

Received 26 November 2003; Revised 7 July 2004; Accepted 19 July 2004; Published online 11 August 2004.

Abstract

Diverse phenotypic associations with the catechol-O-methyltransferase (COMT) Val¹⁵⁸Met polymorphism have been reported. We suggest that some of the complex effects of this polymorphism be understood from the perspective of the tonic–phasic dopamine (DA) hypothesis. We hypothesize that the COMT Met allele (associated with low enzyme activity) results in increased levels of tonic DA and reciprocal reductions in phasic DA in subcortical regions and increased D1 transmission cortically. This pattern of effects is hypothesized to yield increased stability but decreased flexibility of neural network activation states that underlie important aspects of working memory and executive functions; these effects may be beneficial or detrimental depending on the phenotype, a range of endogenous factors, and environmental exigencies. The literature on phenotypic associations of the COMT Val¹⁵⁸Met polymorphism is reviewed, highlighting areas where this hypothesis may have explanatory value, and pointing to possible directions for refinement of relevant phenotypes and experimental evaluation of this hypothesis.