COMT and ALDH2 polymorphisms moderate associations of implicit drinking motives with alcohol use.

Dual process models of addiction propose that drug use behavior is influenced by two distinct but interdependent cognitive-motivational systems (Bechara, 2005; Wiers et al., 2007). One is a controlled or reflective system, governed largely by explicit (i.e., conscious) processes; the other is an impulsive or reflexive system, guided primarily by implicit (i.e., automatic) processes that operate largely outside of conscious awareness (e.g., Bechara, 2005; Kalivas & Volkow, 2005; Wiers et al., 2007). Theoretically, the influence of implicit processes on behavior is partly contingent on the strength of countervailing explicit influences. For example, conditioned drug cues could serve to engage reward-related associative networks, triggering appetitive responses (e.g., craving) through implicit mechanisms. Explicit processes (e.g., conscious deliberation to avoid drug use) can potentially curb these reflexive influences, assuming motivation and adequate self-regulatory resources for doing so (Wiers et al., 2007). Explicit and implicit systems are presumed to reflect largely distinct neural networks, with the former governed predominantly by prefrontal mechanisms and the latter by an incentive network reflecting limbic and ventral-striatal pathways (e.g., Bechara, 2005). Dual process theories also propose that dispositional or situational factors can create “boundary conditions” that moderate the relative influence of implicit versus explicit cognitive processes on behavioral outcomes (Hofmann, Friese, & Strack, 2009). Among many possible moderating factors, executive cognitive functioning has been studied extensively (Barrett, Tugade, & Engle, 2004). Research in this area generally suggests that higher working memory capacity can mitigate the influence of impulsive cognitive processes on various appetitive behaviors, whereas reduced working memory renders impulsive processes more influential (Hofmann et al., 2009). This finding has been extended to alcohol use behavior, such that the association of implicit measures of alcohol motivation with reported consumption is stronger for individuals with relatively lower performance on measures of working memory and response inhibition (Grenard et al., 2008; Houben & Wiers, 2009; Thush et al., 2008). Although genetic influences are theoretically relevant for dual process models of addiction, only one published study has examined genetic associations with implicit measures of alcohol cognitions (Wiers et al., 2009). Results of that study suggested that heavy-drinking males with the G allele of the OPRM1 A118G polymorphism showed stronger automatic motivational tendencies toward alcohol cues than those without the variant (Wiers et al., 2009). This finding was consistent with prior evidence that individuals with the G allele show greater sensitivity to alcohol-induced stimulation and reward (Ray & Hutchison, 2004), suggesting that genetic differences in the endogenous opioid system (implicated in alcohol dependence; Herz, 1997) may be relevant for dual processes models of drinking behavior. The aim of the current study was to extend previous work by evaluating implicit alcohol cognitions in relation to genes with functional relevance for additional systems implicated in alcohol dependence; specifically, executive cognitive functioning and alcohol metabolism. Variation in executive cognitive function is demonstrated to predict risk for alcohol use disorders (Finn et al., 2009) and to moderate associations of implicit alcohol cognitions and drinking behavior (Grenard et al., 2008; Houben & Wiers, 2009). Therefore, our first goal was to evaluate a gene with functional significance for executive cognitive ability. COMT encodes catechol-O-methyltransferase, an enzyme important for the degradation of central nervous system catecholamines and critical for degradation of dopamine in the prefrontal cortex (Bilder et al., 2004). A nonsynonymous G-to-A polymorphism at codon 158 (rs4680) results in an amino acid subtitution (Val-to-Met) in exon 4, which is associated with 3- 4-fold variation in enzymatic activity (Bilder et al., 2004; Winterer & Weinberger, 2004). The high-activity variant (Val) is associated with reduced prefrontal dopamine due to more efficient dopamine clearance, whereas the low-activity variant (Met) is associated with increased tonic dopamine (Winterer & Weinberger, 2004). Notably, functional effects of Val158Met on cognition appear to involve a tradeoff between cognitive stability and flexibility. Presumably due to increased prefrontal dopamine, Met carriers appear to show better performance on working memory tasks requiring cognitive stability, but reduced cognitive flexibility on tasks requiring rapid cognitive shifting, disengagement and/or conflict processing/resolution (Neuhaus et al., 2009; Nolan et al., 2004; Tunbridge, Harrison, & Weinberger, 2006). The Met variant is also predictive of increased limbic activity and reduced processing efficiency in response to emotionally evocative stimuli (Heinz & Smolka, 2006; Tunbridge et al., 2006) and has been linked to anxiety-related phenotypes (Enoch, 2006). Though studied largely in the context of schizophrenia, COMT Val158Met has been implicated in the risk for alcohol use disorders (Bilder et al., 2004; Enoch, 2006; Foroud et al., 2007), such that the Met variant is associated with higher rates of alcohol dependence (Tiihonene et al., 1999; Wang et al., 2001) and social drinking (Kauhanen et al., 2000). Notably, Val158Met was recently linked to post-treatment relapse in alcohol-dependent individuals, such that Met carriers were about twice as likely to relapse in the year following treatment as those without the variant (Wojnar et al., 2009). Though mechanisms underlying increased risk for alcohol use in Met carriers have not been identified, it is proposed that the Met variant could confer increased risk by way of differential dopamine-modulated reinforcement from acute intoxication, diminished ability to cope with negative emotional states, and/or deficits in cognitive flexibility and task switching (Bilder et al., 2004; Enoch, 2006; Oroszi & Goldman, 2004). Of relevance to the current study, the ability to override impulsive processes and/or disengage from the influence of salient appetitive cues is presumed to be important for mitigating the influence of implicit alcohol cognitions on drinking (Grenard et al., 2008; Thush et al., 2008). Therefore, one possibility is that Met carriers would demonstrate stronger associations between implicit measures of alcohol motivation and drinking behavior, perhaps due to a relatively reduced capacity for cognitive flexibility and/or disengaging from emotionally evocative stimuli. Our second goal was to evaluate implicit alcohol cognitions in relation to a variant with functional effects on alcohol metabolism. ALDH2 encodes the mitochondrial aldehyde dehydrogenase (ALDH) enzyme, the principal catalyst for oxidation of acetaldehyde during alcohol metabolism. A single nucleotide substitution at exon 12 (rs671) results in a variant allele (ALDH2*2) that encodes a functionally inactive ALDH enzyme subunit, thereby limiting oxidation of acetaldehyde during alcohol metabolism. ALDH2*2 is nearly exclusive to northeast Asian populations. Compared with the common ALDH2*1 variant, ALDH2*2 is associated with higher levels of post-drinking acetaldehyde, increased sensitivity to alcohol, and a significantly reduced risk for alcohol dependence (Wall, 2005). ALDH2*2 has also been linked to explicit measures of alcohol cognitions, including lower drinking motives and higher self-efficacy for resisting alcohol (Hendershot et al., 2010). Based on these findings, one hypothesis is that individuals with ALDH2*2 might show reduced automatic approach tendencies toward alcohol, and/or weaker associations between implicit measures of alcohol motivation and drinking behavior, compared to individuals without this variant. Whereas most studies incorporating implicit measures of alcohol cognitions have examined general classes of automatic cognitions (e.g., implicit measures of positive or negative attitudes toward alcohol), the current study focused specifically on implicit measures of drinking motives. Drinking motives (Cooper et al., 1995) reflect individual differences in the perceived reinforcement value of alcohol and, when assessed with self-report measures, show strong associations with drinking outcomes (Kuntsche et al., 2005). Further, recent studies have linked explicit (self-report) measures of drinking motives to ALDH2 (Hendershot et al., 2010) and OPRM1 (Miranda et al., 2010). However, implicit measures of drinking motives have not been developed until recently (Lindgren et al., 2010). The current study incorporated Implicit Association Tests (Greenwald, McGhee, & Schwartz, 1998) to evaluate associations among genetic factors (COMT and ALDH2), implicit alcohol cognitions, and drinking behavior. The hypotheses were as follows: a) COMT Met carriers (compared to Val/Val individuals) would show stronger implicit drinking motives, b) those with the ALDH2*1/*2 genotype (compared to ALDH2*1/*1 individuals) would show weaker implicit drinking motives, and c) COMT and ALDH2 genotypes would moderate associations of implicit motives and drinking behavior. Specifically, we predicted that associations of implicit motives with alcohol use would be stronger in the context of genetic variants associated with relatively higher risk (COMT Met and ALDH2*1/*1).