The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes

Abstract

Diverse phenotypic associations with the catechol-O-methyltransferase (COMT) Val158 Met 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 Val 158 Met 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.

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

“…However, the WCST is a complex task involving multiple cognitive functions including hypothesis generation, self-monitoring and error correction, which may limit its ability to discriminate between cognitive stability and cognitive flexibility. 36 Bilder 36 hypothesizes that the cognitive effects of COMT genotype may be underpinned by differential effects on tonic versus phasic dopaminergic transmission 37 such that the presence of Met alleles increases tonic DA transmission and decreases phasic DA transmission subcortically, resulting in increased D1 and decreased D2 transmission in prefrontal cortex. To test this hypothesis, future studies might use tasks that enable more precise segregation of cognitive processes.…”

An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of Δ-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition

“…The apparent inconsistency that the Val allele did not affect THC sensitivity for all cognitive functions may reflect low power for the two-way interaction, but may also be interpreted in the light of the tonic-phasic dopamine theory as suggested by Bilder et al (2004) and Grace (1991). Higher activity of COMT in the prefrontal cortex, associated with the Val allele, may produce a selective decrease in tonic dopamine subcortically, thus initiating an activation of phasic dopamine transmission.…”

“…The COMT gene, mapped to chromosome 22q11, contains a functional polymorphism (COMT Val 158 Met) resulting in two common variants of the enzyme (Val and Met) corresponding to high-and low-activity enzyme, respectively. Increased COMT activity may result in a combination of (i) reduced dopamine neurotransmission in the prefrontal cortex, hypothesized to result in poorer performance of frontally mediated cognitive tasks, in particular working memory and attention (Egan et al, 2001;Meyer-Lindenberg et al, 2005;Rosa et al, 2004) and (ii) increased levels of meso-limbic dopamine signaling hypothesized to result in increased risk for delusions and hallucinations, the core symptoms of psychosis (Akil et al, 2003;Bilder et al, 2004). The work to date therefore suggests that COMT genotype, psychometric psychosis liability, and being a patient with a psychotic disorder moderate the effect of cannabis on psychosis outcomes in the community (Caspi et al, 2005;Henquet et al, 2005a) and that differential sensitivity to cannabis not only involves the positive symptoms of psychosis, but also cognition, in particular memory (D'Souza et al, 2005).…”

Investigation of the COMT Val158Met variant association with age of onset of psychosis, adjusting for cannabis use

“…Cannabis is known to increase dopamine levels in the cortex (Stokes et al., 2010), striatum (Bossong et al., 2015), and the mesolimbic pathway (Oleson & Cheer, 2012). Given its key role in dopamine metabolism, especially in the prefrontal cortex, COMT has been suggested to be a good candidate for gene‐environment interaction effects in psychosis, such as with cannabis (Bilder, Volavka, Lachman, & Grace, 2004). …”