In this study we examined whether laboratory-based findings regarding genetic influences on subjective responses to alcohol and urge to drink generalize to the natural environment. To this end, heavy drinkers, 61% of whom were alcohol dependent, used handheld electronic diaries to monitor drinking episodes for 5 consecutive days. Analyses revealed that carriers of the Asp40 allele of the OPRM1 gene reported greater feelings of vigor and less negative mood during drinking episodes, as compared to homozygotes for the Asn40 allele. This is generally consistent with the a-priori hypotheses and laboratory-based findings by Ray & Hutchison (2004
). Interestingly, the interactions between OPRM1 genotype and eBAC suggested that as BAC increased, carriers of the Asp40 allele reported greater decreases in vigor and greater increases in negative mood, compared to homozygotes for the Asn40 allele. These results suggest that the greater stimulant effects of alcohol, reported by Asp40 carriers in their natural environment, may be dose-dependent and perhaps stronger at low levels of BAC.
The results supported the initial hypothesis that carriers of the long allele of the DRD4 gene would report greater urge to drink but offered no support for the notion that this polymorphism moderates subjective responses to alcohol. The finding that the DRD4-L allele was associated with greater urge to drink after alcohol consumption is consistent with previous laboratory studies (Hutchison et al., 2002
; McGeary et al., 2006
). However, an interaction between DRD4 genotype and eBAC indicated that at higher eBAC urge to drink had a more pronounced increase among homozygotes for the short allele than carriers of the long allele. A recent study used functional imaging (fMRI) to examine the neural correlates of these two polymorphisms upon presentation of alcohol taste cues and a priming dose of alcohol (Filbey et al., 2008
). In this study, carriers of the long allele of the DRD4 VNTR had significantly greater neural response to alcohol taste cues (i.e., cue-exposure) in the orbitofrontal, cortex, anterior cingulate gyrus, and striatum prior to a priming dose of alcohol (i.e., cue-exposure), but not after a priming dose. These findings suggested that the effects of this polymorphism may be in response to alcohol cues and not necessarily the neuropharmacological effects of alcohol ingestion. While the present study cannot disentangle the effects of presence of alcohol cues from its pharmacology, it is consistent with the Filbey et al. (2008
Conversely, the aforementioned imaging study revealed that Asp40 carriers had greater hemodynamic response in mesocorticolimbic areas both before and after a priming dose compared to homozygotes for the Asn40 allele (Filbey et al., 2008
). Thus, the pharmacological effects of alcohol on endogenous opioids in the mesolimbic system (Erickson, 1996; Herz, 1997
; Kreek, 1996
) may be moderated by this polymorphism. These results are relevant to the literature showing that the Asn40Asp allele moderates the effects of naltrexone (Anton et al., 2008
; McGeary et al., 2006
; Oslin et al., 2003
; Ray & Hutchison, 2007
), a pharmacotherapy thought to dampen the reinforcing effects of alcohol (King et al., 1997
; Swift et al., 1994
; Volpicelli et al., 1995
). Additional studies and converging evidence from multiple lines of research (e.g., laboratory-based, clinical trials, EMA-based, neuroimaging) are necessary to more fully elucidate these complex mechanisms of genetic causation and their clinical implications to the etiology and treatment of alcohol use disorders.
Thus, for both the OPRM1 and DRD4 polymorphisms under study, participants’ subjective responses to alcohol were more strongly dose-dependent for carriers of the minor alleles (i.e., Asp40 and DRD4-L), such that these individuals reported overall greater levels of vigor, lower levels of negative mood (OPRM1 Asp40), and stronger urge to drink (DRD4-L) across drinking episodes. Nevertheless, at higher levels of eBAC these individuals reported greater decreases in vigor, increases in negative mood, and lower increases in urge to drink, respectively. Further investigation on the nature of the OPRM1 (and DRD4 VNTR) by BAC interactions seems warranted in order to more fully elucidate the effects of these polymorphisms on subjective responses to alcohol and drinking behavior per se. This is particularly important considering that BAC was estimated and not directly measured in this study and that not all individuals reported drinking episodes at the various possible levels of BAC.
Interestingly, the pattern of OPRM1 Asn40Asp and DRD4 VNTR findings are consistent with Robinson and Berridge’s (1993
) incentive sensitization model of drug motivation. From this standpoint, the ascending corticomesolimbic dopamine circuit is largely responsible for attributions of incentive salience, or “wanting,” whereas opioidergic and other neurotransmitter systems variously subserve the hedonic impact, or “liking,” of both natural and drug rewards (Kelley & Berridge, 2002
; Robinson & Berridge, 1993
). Similarly, in the current study and other recent studies, functional genetic variation in the dopamine system has been associated with more pronounced craving (“wanting”) responses (e.g., Hutchison et al., 2002
; McGeary et al., 2006
; cf. van den Wildenberg et al., 2007b
), whereas functional genetic variation in the endogenous opioid system has been associated with variation in the psychoactive effects of alcohol (Ray & Hutchison, 2004
). This is also consistent with the post-hoc findings from this study suggesting that when controlling for urge to drink, carriers of the Asp40 allele drank 4.73 more drinks per episode than Asn40 homozygous and the OPRM1 × urge to drink interaction suggesting that urge to drink was less strongly associated with actual alcohol consumption among carriers of the Asp40 allele. The findings that urge to drink may be a less potent determinant of drinking behavior among carriers of the Asp40 allele is in line with the dissociation between ‘wanting’ and ‘liking’, such that opioid-mediated processes are thought to be less strongly related to the former and more strongly associated with the latter. Despite this apparent consistency with the incentive sensitization approach and its extensive empirical basis, the literature on both of these polymorphisms remains relatively small and the mechanisms underlying their relationship to alcohol use and misuse remain poorly understood.
Additionally, one may argue that tension-reduction or stress-response dampening models (e.g., Greeley & Oei, 1999
; Levenson et al., 1980
; Sher & Levenson, 1982
) may offer an alternative explanation to the current findings. Nevertheless, negative reinforcement assumes that the levels of negative mood have reached an unpleasant level and the relief from negative mood results in negative reinforcement. That may be especially true in the case in of comorbidity between alcohol use disorders and mood and anxiety disorders, for instance. Conversely, if the levels of negative mood are at a normative level but are then “lifted,” or improved, by alcohol intake then positive reinforcement is thought to occur. In other words, the current data does not allow us to determine how reinforcing these mood changes (i.e., vigor and negative mood) were to each individual. As reviewed by Sher and colleagues (2005
), the relationship between negative affective states and alcohol intake or problems is not a strong one and laboratory-based studies have provided contradictory evidence on the effects of alcohol on negative affect. More specifically, the authors argue that negative affect regulation from drinking may be highly dependent upon intraindividual and situational factors, such as expectancies, genetics, and stressful environments (Sher, Grekin, and Williams, 2005
). This is certainly as much of an empirical question as it is a theoretical one and further research is needed to better understand the underlying structure of the various facets of subjective responses to alcohol as well as their conceptual meaning and predictive utility. Of note, vigor and urge to drink upon consuming the first two alcoholic drinks were significantly positively associated with alcohol consumption within a given episode. These EMA-based findings offer a better understanding the subjective responses that serve as antecedent, as perhaps determinants, of alcohol consumption in the natural environment.
Limitations of the study include the fact that the BAC estimation procedure was not as precise as that obtained in the laboratory and that these results may not generalize to treatment-seeking samples and/or social drinkers. In addition, selection bias in the group of consenters to the DNA analyses resulted in a greater representation of female participants among consenters. Although gender was controlled for in all genetic models, selection bias cannot be completely ruled out. Similarly, non-consenters tended to be heavier drinkers than consenters, and as such, the selection of individuals of very heavy drinking patterns may bias the sample in terms of genetic and phenotypic characteristics related to responses to alcohol. In this study only the initial two drinks of the day were assessed, which may not generalize to the subjective effects of alcohol observed at higher levels of BAC. Nevertheless, the subjective effects of alcohol after the first two drinks may be especially relevant to whether or not individuals escalate their drinking within a given episode, and more generally, in drinking situations. Lastly, the gender by eBAC interaction was examined and accounted for in statistical models as well as in our procedures for estimating BAC. Nevertheless, not all individuals reported drinking episodes at the various levels of BAC, making it more difficult to fully evaluate the effects of gender in the present models.
Strengths include the study’s external validity as it captures subjective responses to alcohol and urge to drink in nearly real-time in heavy drinkers’ natural environment. The current study extends the literature on genetic factors underlying subjective responses to alcohol and drinking urges, constructs that have been typically studied under laboratory conditions and that are relevant to the etiology and treatment of alcohol abuse and dependence. Specifically, this study examines dimensions of subjective responses to alcohol in the natural environment (a) in the context of theory-driven genetic markers; (b) in relation to actual drinking during each episode; and (c) while considering important contextual time-varying covariates. Together, these methodological advantages afford a unique evaluation of subjective responses to alcohol and genetic markers that may underlie their expression. Similar to the distinction between efficacy and effectiveness trials, this study extends laboratory-based findings of the genetics of subjective responses to alcohol into real-world setting using EMA technology.