Understanding the underlying mechanisms that mediate the moderating effects of COMT Val158Met on subjective drug effects, withdrawal severity, and cognitive performance are an important topic for further research. The high COMT enzyme activity associated with Val allele may reduce tonic DA and increase phasic DA release in subcortical areas as well as reduce DA levels in prefrontal cortical areas (55). This reduced tonic DA release in smokers with the Val allele, may be further accentuated by smoking abstinence, which also reduces DA transmission in subcortical regions (56). As a result, the Val/Val genotype may be associated with more severe withdrawal symptoms. In contrast, the enhanced phasic DA release associated with the Val/Val genotype may contribute to greater responses to some of nicotine’s subjective effects. It is unclear why the COMT Val158Met variation was related to particularly the negative or aversive responses to nicotine. Both the aversive and rewarding effects of nicotine are likely be mediated by DA release in the nucleus accumbens, although the exact mechanisms remain to be determined.
