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/lp/springer-journals/effects-of-craving-and-drd4-vntr-genotype-on-the-relative-value-of-CyBjvZ09pc
- Publisher
- Springer Journals
- Copyright
- Copyright © 2007 by MacKillop et al; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
- eISSN
- 1744-9081
- DOI
- 10.1186/1744-9081-3-11
- pmid
- 17309802
- Publisher site
- See Article on Publisher Site
Abstract
Background: Craving for alcohol is a highly controversial subjective construct and may be clarified by Loewenstein's visceral theory, which emphasizes craving's behavioral effects on the relative value of alcohol. Based on the visceral theory, this study examined the effects of a craving induction on the relative value of alcohol as measured by a behavioral choice task. In addition, based on previous evidence of its role in the expression of craving, the influence of DRD4 VNTR genotype (DRD4-L vs. DRD4-S) was also examined. Methods: Thirty-five heavy drinkers (54% male; 31% DRD4-L) were randomly assigned to receive either a craving induction (exposure to personally relevant alcohol cues) or a control induction (exposure to neutral cues), which was followed by an alcohol-money choice task. Participants were assessed for craving and positive/negative affect throughout the procedure, and relative value of alcohol was derived from participant choices for alcohol versus money. DRD4 VNTR status was assessed retrospectively via buccal samples using previously established protocols. Results: Factorial analysis of the craving induction revealed that it was associated with significant increase in craving (p < .001), but not greater relative value of alcohol. Factorial analyses including DRD4 VNTR genotype of did not suggest an influence on reactivity to the craving induction, although this analysis was substantially compromised by small cell sample sizes. Continuous analyses revealed that craving was significantly associated with the relative value of alcohol (p < .05) and possession of the DRD4-L allele further amplified this relationship (p < .001). Conclusion: These results are interpreted as generally supporting Loewenstein's visceral theory of craving and evidence of a functional role of DRD4 VNTR genotype in the expression of craving for alcohol. Methodological limitations, mechanisms underlying these findings, and future directions are discussed. Page 1 of 12 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 [25-27]]. This includes one of the visceral theory's central Background Despite the long history of research on craving for alcohol predictions, that craving increases the relative value of a [e.g., [1]], the functional relationship between craving and substance, which has received provisional empirical sup- both alcohol use and post-treatment relapse remains port in a number of studies. These studies have largely highly contentious [2,3]. This controversy is, in part, a been in reference to tobacco dependence, where evidence result of considerable ambiguity in the data connecting that craving can be understood in measures of economic craving and alcohol misuse. Although alcohol dependent value has been obliquely supported by several laboratory individuals readily report experiencing cravings for alco- studies using craving-related manipulations (e.g., hol [4,5], the associations between self-reported craving enforced abstinence) that resulted in increases in the rela- and actual alcohol use in human laboratory studies have tive value of smoking [28-30]. However, because these been equivocal [for a review, see [6]; cf. [7,8]]. Similarly, studies were not intended to directly test the visceral in clinical research, a number of retrospective studies have account, the majority lack critical variables, such as the reported a negligible role of craving in relapse [9-11]. subjects' level of craving, or did not report the relationship Given the ambiguous empirical data, it is not surprising between craving and the relative value of smoking. that there is little consensus as to the role of craving in alcohol use disorders [2,12]. More convincingly, three studies have directly examined and reported the relationship between craving and the rel- The present study sought to better understand craving for ative value of smoking with generally positive results. In alcohol using a novel theoretical approach, Loewenstein's an initial study, Willner et al. [31] found a significant [13,14] visceral theory of addiction. The visceral theory is increase in the relative value of tobacco following depriva- a hybrid theory that integrates decision theory [e.g., tion using a progressive-ratio operant task. Similarly, Per- [15,16]] and learning theory [e.g., [17,18]] via a common kins et al. [32] found a positive association between pathway of behavioral economics. From this perspective, craving and subjects' perceived cash value of tobacco, addiction is an extreme example of a wide array of behav- although craving was not associated with effort expended iors that are largely controlled by visceral factors, or drive on an operant task. Finally, Sayette et al. [33] conducted a states such as hunger, thirst, sexual desire, or, in the case multi-dimensional assessment of cue-elicited craving and of addiction, craving. The decision to use a substance is found a significant association between craving and the considered to be the final determinant of substance use, relative value of smoking as measured using a forced- which is itself guided by the value of the substance relative choice self-administration task. to all other available choices (i.e., relative value). How- ever, the relative value of a substance is not a static prop- Comparatively little research from this perspective has erty and it is proposed to be substantially influenced by a been conducted in reference to craving for alcohol, with number of variables, most prominently, craving. Specifi- only one study in that domain. In the context of a labora- cally, the visceral theory proposes that it is not simply the tory study on the mechanisms of naltrexone pharmaco- experience of craving that precipitates substance use, but therapy, O'Malley et al. [7] administered a priming dose rather it is the effects of craving, including increased rela- of alcohol and then used a self-administration paradigm tive value of the substance, increased discounting of that permitted participants to "buy" drinks. Post-priming delayed rewards, and narrowed temporal perception, subjective craving was found to significantly correlate among others. Over time, substance misuse is proposed to with the number of alcoholic beverages chosen (and be a function of these effects recurrently biasing an indi- money foregone), thus converging with the majority of vidual's behavior toward continued substance use over evidence from tobacco research that subjective craving can more salubrious options. Importantly, by virtue of its be understood in terms of relative value. Considered emphasis on craving's effects on the value of the sub- together, the preceding studies on craving for tobacco and stance, Loewenstein's visceral theory is distinct from other alcohol suggest that the visceral theory is a promising contemporary theories of craving that emphasize craving approach for understanding craving. To further test the as a classically conditioned response [18-20], an affective theory, the first goal of the current study was to examine process [21,22], or a cognitive process [23]. In addition, the effects of a craving induction on the relative value of the visceral theory can be clearly distinguished from alcohol. approaches that propose craving to primarily reflect the interruption of automatized addictive behaviour, and, as The second goal of the current study sought to examine a a result, to be largely epiphenomenological [6,24]. potential neurogenetic variable that may influence the relationship between craving and the relative value of Although the visceral theory has not been subjected to alcohol. There is considerable evidence that one of the substantial direct empirical testing, a number of its predic- major neural substrates of craving is mesolimbic tions have been borne out by the empirical literature [e.g., dopaminergic neurotransmission [34,35], although not Page 2 of 12 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 exclusively [e.g., [36]]. Moreover, there is recent evidence Methods that alleles of the gene responsible for the dopamine D Participants receptor, which is localized within the limbic system, may Participants were recruited using posted advertisements play an important role in the expression of craving for and classroom/email solicitations at the State University alcohol [37-40]. Specifically, the D receptor gene (DRD4) of New York at Binghamton. They were required to be has a variable number of tandem repeats (VNTR) poly- heavy drinkers, defined as drinking at least 20+/14+ morphism in exon 3, with common variants of 2, 4, and standard drinks per week for males/females [50] and of 7 repeats [41], and there is evidence that possession of a legal age for alcohol consumption (21 years old in New long allele (7 repeats or more; DRD4-L) confers func- York State). Since the multimodal craving induction was tional differences in dopamine neurotransmission [42- oriented around beer, prospective participants were 44]. Vis-à-vis craving, previous studies have demonstrated required to report beer as both a favorite and most often that DRD4-L status positively moderates the effects of consumed alcoholic beverage, and to rate their enjoyment both an alcohol cue exposure [37,40] and priming dose of of beer seven or greater on a 10-point Likert-type scale. alcohol on craving [38]. Similar interactions between Participants were compensated with $10, plus any money DRD4 VNTR genotype and craving have also been found selected during the choice task. in laboratory studies of smoking [45], heroin addiction [46], and binge eating [47]. Although the exact role of the Thirty five (54% male; mean age = 21.83 [SD = 1.12]) DRD4 VNTR genotype remains unclear, these studies sug- heavy drinkers were enrolled in the study. Male partici- gest that possession of a long version of the DRD4 VNTR pants drank an average of 36.32 (SD = 12.98) drinks/week genotype may also enhance the effect of craving on the rel- and female participants drank an average of 21.00 drinks/ th th ative value of alcohol. week (SD = 6.54). These levels reflect the 97 and 98 per- centiles of alcohol consumption for this cohort [51]. The Thus, this study was a preliminary investigation using the mean AUDIT score was 14.2 (SD = 5.58) and 100% of par- visceral theory as a framework for concurrently examining ticipants scored an 8 or higher, the previously validated the influences of a craving induction and DRD4 VNTR criterion for hazardous drinking [52]. Eleven (31%) par- genotype on the relative value of alcohol. Heavy drinkers ticipants were classified as DRD4-L based on possession were enrolled in a laboratory protocol and randomized to of at least one version of the DRD4 VNTR allele with seven receive either a craving induction (i.e., exposure to per- or more repeats. Median household income was sonally relevant alcohol cues) or a control induction (i.e., $100,000 (IQR = $65,000–$135,000). In terms of race/ exposure to neutral cues), followed by an alcohol-money ethnicity, 83% of the sample was Caucasian, 14% of the choice task to assess the relative value of alcohol. A cue sample was Hispanic, and 3% of the sample was Asian. exposure approach was employed as the craving induc- tion because it has been robustly validated for inducing Experimental design craving in the laboratory [for a review, see [48]], and has The study used a one-way two-group between-subjects the advantage of not including the array of concomitant design. Upon enrollment, participants were randomly physiological effects of induced withdrawal [e.g., [30]] or assigned to receive either the craving induction or control mild intoxication [7]. Moreover, the visceral theory pro- induction and all underwent the relative value of alcohol poses that the most important form of craving is cue-elic- task immediately following the post-induction assess- ited craving that persists beyond treatment [13,14]. Based ment. In considering DRD4 VNTR influences, the design on the visceral theory, the craving induction was predicted was elaborated to 2 (craving induction/control induction) to be associated with greater relative value of alcohol com- × 2 (DRD4-L/DRD4-S) quasi-experimental factorial pared to the control induction, and the absolute level of design. The latter was quasi-experimental because subjects craving independent of induction was predicted to be sig- cannot be randomly assigned to genotype. In addition to nificantly associated with relative value of alcohol. the factorial design, based on the visceral theory's empha- Although the existing literature on DRD4 VNTR effects is sis on the importance of the absolute level of craving relatively small, DRD4-L status was predicted to both pos- [13,14], continuous relationships were also examined itively moderate the effects of the craving induction, repli- and are described further in the Data Analysis section. cating two previous studies [37,40], and the continuous relationship between craving and the relative value of Measures alcohol. Based on theoretical interest in the relationship Drinking days questionnaire (DDQ) between craving and affect [21,22,49], positive and nega- The DDQ is a seven-item, face-valid measure of an indi- tive affect was concurrently assessed throughout the study, vidual's average alcohol consumption per week. Its seven but given ambiguous associations in previous studies items assess the typical amount consumed for each day of [e.g., [49]], no directional predictions were made. the week and it has been shown to have adequate psycho- metric properties [53,54]. Page 3 of 12 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 Alcohol use disorders identification test (AUDIT) one ninth of the beer, which was an appropriate size for a The AUDIT [52] is a ten-item self-report screening meas- sip. In addition, this unit was easily conveyable to partic- ure that evaluates various quantitative and symptom- ipants. The first choice was between a sip of alcohol and related aspects of drinking. The AUDIT yields a score from $1, and the overall domain of potential choices and incre- 0–40; a score of 8 or above indicates hazardous drinking, ments was as follows: $.01, $.02, $.05, $.10, $.25, $.50, $1 or drinking at risk for negative psychosocial conse- (starting point), $1.50, $2, $2.50, $3, $3.50, $4, $4.50, quences. The AUDIT has been extensively validated in and $5. terms of psychometric properties with high sensitivity and specificity [52], and had a coefficient α of .74 in this sam- The task used an adaptive adjusting procedure based on ple. the participant's responses over the course of the nine choices. If the participant chose alcohol, the amount of Subjective craving money offered on the next choice was increased by one A single item measure of craving [e.g., [33,35]] was increment; if the participant chose money, the amount of employed in this study and followed recommendations money offered on the next trial decreased by one incre- for conceptualizing craving on a continuum of urges for ment. Relative value of alcohol was defined as the value alcohol [56,57]. In this case, a 100-point Likert-type scale that reflected the individual's change in preference from of urge to drink was used with four anchoring comments alcohol to money and vice versa [i.e., "crossover" point; ("I don't want a beer at all," "I don't want a beer very much," [29]]. Specifically, relative value of alcohol was defined as "I'd like a beer now," and "I'd REALLY like a beer right the mean of the smallest amount of money chosen over a now!!!") to enhance the likelihood of similar interpreta- sip of alcohol (inferring that alcohol was worth less than tion of the scale by participants. The first and last com- that amount) and the largest amount of money over ments were placed at the low and high ends of the scale, which alcohol was chosen (inferring that alcohol was respectively, and the two intermediate comments were worth more than that amount). Of note, the critical beneath the numbers 35 and 70, respectively. dependent variable in this study was relative value of alco- hol, not the absolute amount of money earned in the task. Positive and negative affect schedule (PANAS) As a result of the adjusting procedure in the task, there was Positive and negative affect were assessed using the not a linear relationship between the number of choices PANAS [58]. The PANAS is a 20-item measure of transient made for money and the amount of money earned. mood that has undergone extensive previous psychomet- Equally, since the adaptive adjusting procedure was ric validation [58,59]. In this sample, under neutral con- responsive to choice, the absolute numbers of choices for ditions, the positive affect subscale of the PANAS money or alcohol were redundant with relative value of generated a baseline coefficient α of .87 and the negative alcohol and not used as dependent variables. affect subscale generated a baseline coefficient α of .85. Genotyping Relative value of alcohol task A sample of buccal cells was collected from each partici- The relative value of alcohol task was based on previous pant using an oral swab, following previously published methods used to assess relative value in behavioral eco- procedures [37]. Participants swabbed their cheeks with nomic research [29,60,61]. Because craving states are rela- three cotton swabs and then rinsed their mouths with 10 tively transient [62,63] and delays of rewards substantially ml distilled water. The swabs and wash were placed in a influence their relative value [60], the task was designed to sterile 50 ml polypropylene tube containing 500 µl of 1 M be as short as possible (~90 seconds) and all alcohol and/ Tris-EDTA buffer (1 M Tris-HCl, 200 µM disodium EDTA, or money selected was provided immediately following pH 8.0), 500 µl of 5% sodium dodecyl sulfate (SDS), and the task. To maximize the validity of the choice task, par- 100 µl of 5 M sodium chloride. The tubes were refriger- ticipants were provided with actual alcohol and/or money ated until DNA was extracted. To extract the DNA, protei- based on their choices. nase K (0.2 mg/ml) was added to the tubes and the tubes were incubated at 65°C for 60 min. The swabs were Procedurally, each participant's relative value of alcohol removed and residual lysis buffer was extracted by centrif- was empirically defined in monetary terms using a series ugation (using a 3-ml syringe barrel and sterile 15 ml of choices to determine the average amount of money a tube) for 5 minutes at 1,000 × g. The residual fluid was participant would "pay" for a sip of alcohol. Participants added back to the original sample. An equal volume of completed nine choices between a 1.5-ounce sip of the isopropyl alcohol was then added to each tube, the con- participant's favorite beer (alcohol) and varying amounts tents were mixed, and the DNA was collected by centrifu- of money to determine this point. This sip volume was gation at 3,500 × g for 10 min. The DNA pellet was rinsed selected because the total volume of alcohol available was once with 1 ml of 50% isopropyl alcohol and allowed to one standard beer and 1.5 ozs represented approximately air dry. The pellet was resuspended in 1 ml of 10 µM TRIS- Page 4 of 12 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 HCl, 10 mM EDTA buffer (pH 8.0) and place in a 1.8-ml contingency between not drinking and early departure, cryovial. The concentration of DNA was calculated from and that they would be compensated $10 but could also the absorbance at 260 nm. Samples were stored at -70°C potentially receive additional money. In addition, partici- until used. The collection and extraction rate was 100%; pants were informed that they would have access to alco- all participants were retrospectively genotyped. hol [65] and would be required to endorse that there were no significant reasons why they could not drink if they The 48 basepair VNTR in exon 3 of the DRD4 gene was chose to during the session (e.g., medication, athletic assayed using primer sequences: forward, 5'-AGGACCCT- event, examination). In advance of the experimental ses- CATGGCCT TG-3' (fluorescently labeled), and reverse 5'- sion, participants were sequentially randomized to receive CGACTACGTGGTCTACTCG-3' [64]. Genotyping success the craving or control induction. rate was 100%. Consistent with previous research [37-40], participants who were homozygous or heterozygous for During the experimental session, participants initially an allele of seven repeats or longer were classified as provided informed consent in a neutral experimental DRD4-L and all other participants were classified as room and were assessed for breath alcohol. If any breath DRD4-S. The allele frequencies of the sample are pre- alcohol was detected, the session would be terminated sented in Table 1. and they would be rescheduled; no participants required rescheduling. Participants completed the alcohol use, Procedure craving, and affect measures. They were then escorted to All study procedures were approved by the Human Sub- either the alcohol or neutral cue exposure room and jects Research Review Committee at the State University of underwent the craving induction or control induction. New York at Binghamton. The experiment involved one laboratory session that took place in the afternoon and The craving induction consisted of exposure to an array of lasted 90-minutes. Participants were informed that the personally relevant alcohol cues, including visual, olfac- session would last the full duration to avoid any perceived tory, tactile, imaginal, and proprioceptive cues. Partici- pants were introduced into a dimmed laboratory room (8 ft × 6 ft × 8 ft [2.44 m × 1.83 m × 2.44 m]) decorated with Table 1: DRD4 VNTR allele and genotype frequencies; percentages do not always add to 100 due to rounding error. beer-related paraphernalia (posters and advertisements of beer, barroom trifolds, empty beer bottles). A Research Allele/genotype n % Assistant (RA) then brought a bottle of the participant's favorite beer and poured it into a beer glass. Participants Allele were then left alone for 60 seconds to observe the array of 2811.4 cues. After one minute, the RA returned and informed the 334.3 participants that they would be asked to listen to an imag- 44665.7 511.4 inal scene. In addition, participants were told that during the scene they would be asked to smell the beer from time 71115.7 to time. To establish the correct behavior, participants were then asked to lift the beer to their nose and take five 911.4 inhalations of the smell of the beer. The RA then provided Total 70 99.5 instructions for listening to the scene and left the room, Genotype observing via a one-way window that the participant cor- 2-2 1 2.9 4-2 4 11.4 rectly followed the scene-related instructions. Over the 7-2 2 5.7 course of the scene, participants were asked to hold the 4-3 2 5.7 beer up to their nose and deeply inhale the smell of the 7-3 1 2.9 beer for five seconds on five occasions (total olfactory 4-4 16 45.7 exposure with practice = 30 seconds). The imaginal scenes 5-4 1 2.9 were developed based on previous research on imaginal 7-4 6 17.1 9-4 1 2.9 scenes in cue reactivity research [66,67] and described 7-7 1 2.9 common environmental, interpersonal, and affective con- Total 35 100.1 texts of drinking, as well as evocative descriptions of the Genotype Classification orosensory properties of beer. Participants were matched DRD4-L 11 31.4 to their favorite brand of beer [63] and were also matched DRD4-S 24 68.6 to the imaginal scenes that related to their most common Total 35 100 reason for drinking from among seven possibilities: relax- ation, happiness, enjoyment of the taste, anger, boredom, DRD4-L subjects have at least one allele that is 7 repeats or longer; DRD4-S participants have both alleles shorter than 7 repeats. sadness, anxiety, or habit. Favorite beer and appropriate Page 5 of 12 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 imaginal scene had been assessed during screening; 32 was determined by examining the initial regression model participants received the happy scene, 2 received the fit (R , F-ratio) and relative improvement of the model fit , F-ratio) in subsequent blocks. Where multiple vari- bored scene, and 1 received the sad scene. The control (∆R induction was matched in each respect but took place in a ables were included in a multiple regression block, each different room and all cues, including imaginal scene, variable was evaluated by examining the significance of were oriented around consuming water. For both groups, the variable coefficient. Follow-up analyses were con- the cue exposure periods were equivalent (~8 min). ducted to examine the possibility of population stratifica- tion [69], a "third variable" confound based on Following the cue exposure, participants completed the differential associations between a given phenotype and craving and affect measures a second time, and then com- racial/ethnic differences. For all significant genetic find- pleted the relative value of alcohol task. Participants were ings, population stratification was addressed by re-exam- informed that they now had the opportunity to choose ining the findings within the largest single racial group (a either a 1.5 oz sip of their favorite beer or various amounts group with minimized racial admixture). of money. The volume of the sip was demonstrated using water in a glass. In addition, the participants were Results informed that as soon as the task was over, they would be Baseline analyses provided with the total amount of alcohol and/or money All baseline dependent variables were adequately nor- that they chose. The provision of the alcohol/money con- mally distributed. No data were missing and no outliers cluded the experimental portion of the procedure. Partic- were identified. Using one-way analyses of variance ipants then returned to an undecorated experimental (ANOVAs), no significant baseline differences were evi- room (without either alcohol or water cues) and under- dent between participants randomized to the two induc- went the genotyping procedure, before relaxing in that tions on the following variables: drinks/week, AUDIT room for the remainder of the session (approximately one score, craving, positive affect, and negative affect (all ps > hour). This period was used to ensure that no participants .20). One-way ANOVAs also revealed no significant differ- would leave the study intoxicated. At the conclusion of ences between DRD4-L and DRD4-S genotypes on the fol- the session, a debriefing was conducted and breath alco- lowing variables: drinks/week, AUDIT score, craving, hol was established at 0.00%. All genotyping was con- positive affect, and negative affect (all ps > .20). Because of ducted retrospectively, following the completion of the potential relevance of income, drinks/week, and level enrollment. of problems with alcohol (i.e., AUDIT score) to the dependent variables, these variables were also initially Data analysis examined as potential covariates using simple regressions. All baseline data were examined for outlying data points Coefficient estimates revealed that income, drinks/week, and distribution normality. All participants were exam- and AUDIT were not significantly associated with post- ined on alcohol use and other self-report variables to eval- induction craving (ps > .10), relative value of alcohol (ps > uate potential baseline differences as a result of induction .20), and positive affect (ps > .20). However, drinks/week assignment or DRD4 VNTR genotype. Principal analyses was significantly negatively associated with post-cue expo- used hierarchical multiple regression to examine the sure negative affect (β = -.52, p < .01) and was included as influence of covariates, induction type, genotype, and a covariate in the subsequent negative affect analyses; induction-by-genotype interaction; the latter term was income and AUDIT score were nonsignificantly associated examined for evidence of a moderating genetic influence with post-induction negative affect (ps > .14). [68]. Following the factorial analyses, continuous analy- ses were conducted between the experiential variables and Influences of the craving induction and subjective craving on the relative value of alcohol the relative value of alcohol. The difference between the factorial and continuous analyses was that the former Induction effects were examined using hierarchical multi- used the induction type (i.e., craving versus control induc- ple regression to sequentially examine the influence of tion) as an independent variable, whereas the latter used covariates and the effects of the experimental manipula- the participants' actual values for the experiential varia- tion, with the post-induction values of a variable serving bles (i.e., craving and affect) as an independent variable. as the dependent variable, its pre-induction level entered Both factorial and continuous approaches were employed as a covariate in a first block (with the exception of relative because Loewenstein's [13,14] visceral theory proposes value of alcohol, which had no baseline level), and induc- that the absolute level of craving is the most significant tion type entered into a second block. For the effects of the determinant of the relative value of alcohol and a contin- craving induction, the covariate model was significant (R uous analysis addressed this more directly. Specific ana- = .54; F (1, 33) = 38.35, p < .001), indicating that baseline lytic strategies for each portion of the study are provided craving was significantly associated with post-induction in the Results section. In all cases, statistical significance craving. The addition of the induction type in a second Page 6 of 12 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 model significantly improved the model (∆R = .17, F (1, Influences of DRD4 VNTR genotype 32) = 18.52, p < .001) and reflected a significant increase To examine the influence of DRD4 VNTR genotype, in craving for individuals receiving the craving induction DRD4 VNTR status and the induction-by-genotype inter- compared to the control induction, as depicted in Figure action term were added to the preceding hierarchical mul- 1. For positive affect, the covariate model was significant tiple regression analyses of induction effects. Specifically, (R = .88, F (1, 33) = 261.79, p < .001), but the addition the post-induction value of a variable served as the of induction type did not significantly improve the model dependent variable, its pre-induction level was entered as (∆R = .00, F (1, 32) = .05, p > .80). For negative affect, the a covariate in a first block (with the exception of relative covariate model including both drinks/week and negative value of alcohol, which had no baseline level), induction affect was significant (R = .77, F (2, 32) = 54.80, p < .001), type was entered in a second block, and genotype and the but the addition of induction type did not significantly interaction term were entered in a third block; DRD4 improve the model (∆R = .00, F (1, 31) = .23, p > .60). VNTR status was coded as DRD4-S = 1 and DRD4-L = 2. Coefficient estimates for the model revealed a significant Frequencies of genotypes revealed the following cell sam- association with baseline negative affect (p < .001) and a ple sizes for the factorial analyses: craving induction- marginally significant association of drinks/week (p = DRD4-S = 10; craving induction-DRD4-L = 8; control .10). In terms of the effect of the craving induction on the induction-DRD4-S = 14; control induction-DRD4-L = 3. relative value of alcohol, no significant effect was evident Given the preceding cell sizes, particularly the latter, the 2 (R = .01, F (1, 33) = .02, p > .80). × 2 factorial analyses had very limited power but were nonetheless conducted. In terms of craving, the addition Following the factorial analyses (i.e., induction condi- of genotype and induction-by-genotype interaction term tion), continuous analyses were conducted between the did not significantly improve the model (∆R = .01, F (2, experiential variables (i.e., craving and affect) and the rel- 30) = .39, p > .65), as was the case for relative value of ative value of alcohol using the same regression-based alcohol (∆R = .08, F (2, 31) = 1.24, p > .40), positive affect approach, but with post-induction variable values serving (∆R = .00, F (2, 30) = .10, p > .80) or negative affect (F (2, as the independent variable. Continuous examination of 29) = .09, p > .80). the relationship between post-cue exposure craving and the relative value of alcohol revealed a significant associa- The issue of small cell sample size did not apply to the tion (R = .15, F (1, 33) = 5.711, β = .38, p < .05), reflecting continuous analyses and, in the case of craving, the addi- a positive relationship between craving and relative value tion of DRD4 VNTR status and the interaction term 2 2 of alcohol, as depicted in Figure 2. Neither positive (R = resulted in a significant improvement of the model (∆R = .00, F (1, 33) = .00, p > .90), nor negative affect (R = .00, .22, F (1, 33) = 5.22, p = .01). Variable coefficients are pro- F (1, 33) = .00, p > .90) were significantly associated with vided in Table 2 and revealed that this improvement was relative value of alcohol. accounted for by a significant association for the craving- $2.00 $1.80 Craving Induction $1.60 Control Induction *** 50 $1.40 $1.20 $1.00 30 $0.80 $0.60 $0.40 $0.20 $0.00 0 10 2030 4050 6070 8090 100 Baseline Post-Induction Urge to Drink (0-100) E and co al Figure 1 fcohol fects of the craving indu ntro ; *** l ind p < .001 uction (neuction tral cues (per ) o sonalized a n urge (i.e lcohol cues) ., craving) for Continuous a hol an choice task; Figure 2 d the relative value βs = .38, sociation p < .05 between of alcohol urge (i from an .e., craving) f alcohol-o mon r alco- ey Effects of the craving induction (personalized alcohol cues) Continuous association between urge (i.e., craving) for alco- and control induction (neutral cues) on urge (i.e., craving) for hol and the relative value of alcohol from an alcohol-money alcohol; *** p < .001. choice task; β = .38, p < .05. Page 7 of 12 (page number not for citation purposes) Urge to Drink (0-100) Relative Value of Alcohol Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 by-genotype interaction. The interaction effect is depicted in Figure 3 and reflected a relationship such that the influ- $2.00 ence of craving on the relative value of alcohol was dispro- $1.80 portionately high for DRD4-L individuals. No significant $1.60 independent effects or moderating effects of DRD4 VNTR $1.40 status were evident for positive (∆R = .13, F (2, 31) = $1.20 2.27, p > .10) or negative affect (∆R = .09, F (2, 31) = 1.50, $1.00 p > .20). $0.80 Population stratification $0.60 The likelihood of population stratification was considered $0.40 low because there is no evidence to date of population $0.20 stratification for the phenotypes under consideration (i.e., $0.00 craving, relative value of alcohol, affect). In addition, the 0 20 40 60 80 100 120 140 160 180 overall sample in this study was relatively small and the Urge-by-Genotype Interaction Term large majority of participants were of the same race (Cau- casian); proportions of participants by genotype and by Association between the craving by DRD4 int < .01) Figure 3 eraction term and the relative value of alcohol ( VNTR β genotype = 1.70, p race are shown in Table 3. Nonetheless, to address the Association between the craving by DRD4 VNTR genotype interaction term and the relative value of alcohol (β = 1.70, p possibility of population stratification, the significant < .01). genetic findings were re-conducted using only the Cauca- sian participants, which revealed the same pattern of find- ings as the principal analyses. The preceding combined model (i.e., craving, genotype, craving-by-genotype inter- condition, craving was significantly associated with the action) was significant (p < .001), neither craving, nor relative value of alcohol. Parallel findings were evident DRD4 VNTR coefficients were independently significant when considering the influence of DRD4 VNTR genotype. (ps > .30), and the interaction coefficient was significant DRD4-L status did not significantly moderate the effects (p < .05), reflecting the same positive relationship. Formal of the alcohol cue exposure, but when considered contin- tests of population stratification using genomic control uously, DRD4 VNTR genotype significantly moderated were not conducted. the relationship between craving and the relative value of alcohol. The form of this relationship was such that as Discussion craving increased, DRD4-L individuals exhibited a dispro- This preliminary examination of the influences of craving portionately greater relative value of alcohol. Across the for alcohol and DRD4 VNTR genotype on the relative procedures, affect was not influenced by the craving value of alcohol generated mixed results. As anticipated, induction and was not associated with the relative value the craving induction resulted in a significant increase in of alcohol. To most clearly discuss these findings, we will subjective craving compared to the control induction, but first consider the specific findings relating to the craving contrary to predictions, it was not associated with greater induction and will then consider the role of DRD4 VNTR relative value of alcohol. However, when the data were genotype. considered continuously, independent of experimental Effects of the craving induction Table 2: Associations between craving, DRD4 VNTR genotype, With regard to the effects of the craving induction com- and the interaction with the relative value of alcohol. pared to the control induction, the discrepancy between the factorial and continuous findings provides only mixed Variable BSE B β R support for the visceral theory. On one hand, the lack of effect of the alcohol cue exposure is in direct contrast to Craving Model 0.15 what the visceral theory would predict, but, on the other Craving 0.007 0.003 .38* Combined Model 0.36 hand, the significant continuous association between Craving -0.015 0.008 -0.86 craving and relative value is consistent with the visceral DRD4 VNTR Genotype -0.767 0.387 -0.77 theory's prediction that the absolute level of craving deter- Craving × Genotype Interaction 0.018 0.007 1.70** mines the relative value of a commodity. Although these findings appear to be contradictory, they may be under- Regression coefficient estimates for the craving model including only stood in the context of the cue exposure craving induction craving, and for the combined model including craving, DRD4 VNTR itself. Although the cue exposure paradigm typically gen- genotype, and the interaction term with the relative value of alcohol as the dependent variable. Unstandardized (± SE) and standardized erates significant increases in craving in aggregate, there is beta weights are provided, with the total variance accounted for by considerable variation in participants' reactions and in the the model (R ) and statistical significance; * p < .05, ** p < .01. Page 8 of 12 (page number not for citation purposes) Relative Value of Alcohol Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 Table 3: Genotype by race/ethnicity. same as those described in the preceding section, it is also important to note that the study was relatively small in Caucasian Hispanic Asian general and retrospective genotyping resulted in very few subjects in one cell in the induction-by-genotype factorial DRD4-S (n = 24) 79% 17% 4% analyses. As a result, the factorial genetic analyses had very DRD4-L (n = 11) 91% 9% 0% low statistical power, substantially limiting the interpreta- bility of those findings. Importantly, rather than interpret- ing the lack of moderating effect of DRD4 VNTR genotype absolute levels of craving that are reported [48,49]. This is on reaction to alcohol cues as diverging from previous compounded by the fact that participants report a wide findings [37,40], it appears more prudent to conclude that array of levels of craving in general prior to the procedure, this study could not fully test that hypothesis. which contributes to the overall heterogeneity. For exam- ple, in the current study, craving at baseline ranged from In contrast, in the continuous analyses where power was 3 to 79 out of 100. Thus, although subjects receiving the not limited by cell size, the data conformed to predictions. alcohol cue exposure may have reported greater craving in As self-reported craving increased, those individuals pos- aggregate, it appears that was still sufficient heterogeneity sessing the long variant exhibited greater valuation of between the two groups for that effect to not translate into alcohol on the behavioral task. These data are broadly a significant effect on relative value. consistent with previous studies that have suggested that DRD4-L status is associated with amplified expression of In addition, some additional methodological considera- craving for alcohol [37-40], as well as other appetitive tar- tions may be relevant to no significant effect of the craving gets, such as cigarettes [45], heroin [46], and food [47]. Of induction on the relative value of alcohol. First, although note, although the threat of population stratification is the relative value task was intentionally designed to be low in general [69] and was considered to be low in this short and provide immediate tangible rewards, it could study, this was confirmed by replicating the principal only capture one facet of relative value, which is itself a findings in the subsample reporting Caucasian ancestry. multidimensional construct [70,71]. Second, the relative value of alcohol task only used a maximum of one stand- From a mechanistic standpoint, these findings are consist- ard alcoholic beverage, which would have relatively lim- ent with Hutchison et al.'s [45] proposal that possession ited psychoactive effects and may have affected of a DRD4-L allelic variant enhances an individual's sen- participant's valuation of the beverage. Third, the task was sitivity to dopaminergic rewards, including alcohol use. administered on only one occasion because it directly pro- Although characterizing the functional significance of vided alcohol which would have affected subsequent per- polymorphisms of the DRD4 VNTR genotype remains an formance. However, as a result, it could not be active basic research question [72], Hutchison et al. [45] administered on multiple occasions and thus did not pro- propose that this influence may be via functional differ- vide a baseline relative value of alcohol. Each of these ences between the polymorphisms in accumulation of aspects of the methodology could have contributed to the cyclic adenosine monophosphate (cAMP) in response to lack of effect in the factorial analyses and should be con- dopamine agonism. D receptors are members of the D 4 2 sidered in future studies. receptor family and, as such, inhibit cAMP formation, however, the long DRD4 VNTR variant permits two to Despite these potential explanations for the factorial find- three times greater accumulation of cAMP [32]. As a result, ings, performance on the relative value of alcohol task was DRD4-L individuals may be inferred to have chronically nonetheless sensitive to variation in craving in the contin- elevated levels of cAMP, which, in conjunction with eleva- uous analyses, which accords with the prediction of the tions of additional downstream transcriptional factors, visceral theory. Indeed, a cornerstone of the theory is that has been associated with enhanced sensitivity to the absolute level of craving is a critical determinant of dopaminergic rewards in a number of studies using ani- behaviour, which is also supported by the current data mal models [73-75]. Moreover, such effects are specific to where overall experiential craving was more important increased in cAMP in the nucleus accumbens, which is than the experimental manipulation. both a structure where D receptors are localized [76] and one of the key putative substrates of reward motivation Influences of DRD4 VNTR genotype [34,35]. However, despite the plausibility of differences in Like the effects of the craving induction, the influence of intracellular cAMP being responsible for the observed DRD4 VNTR genotype was mixed, exhibiting a negligible interaction, because the functional role of polymor- influence in the factorial analyses but a substantial influ- phisms of the DRD4 VNTR genotype has not been fully ence in the continuous analyses. Although potential characterized [72] and the literature on DRD4 VNTR methodological explanations for this discrepancy are the influences on craving in humans is relatively small, it is Page 9 of 12 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:11 http://www.behavioralandbrainfunctions.com/content/3/1/11 important to underscore that considerable further Authors' contributions research is necessary to understand these relationships. JM conceived the study, developed the procedures, ana- lyzed the data and was the principal author of the manu- Future directions script. DM contributed to the conception of the study, ran Based on this preliminary study, further examinations of all participants, and contributed to data interpretation the utility of the visceral theory for understanding craving and manuscript preparation. JMc genotyped all partici- as a motivational factor appear to be warranted. Method- pants, contributed to data interpretation, and participated ologically, as noted above, subsequent studies would do in manuscript preparation. SAL contributed to the con- well to consider behavioural economic methodologies ception of the study, data interpretation, and manuscript that allow for dynamic point-to-point assessments of rel- preparation. All authors have read and approved this ative value that can incorporate multiple facets of value manuscript. and potentially more meaningful amounts of alcohol. Clearly, larger sample sizes would permit more exhaustive Acknowledgements We thank Drs. Peter M. Monti and Steven J. Lynn for their helpful com- examinations of genetic contributions to craving, both in ments on earlier versions of this article, and thank Chinatsu McGeary for terms of statistical power and the alleles under considera- assistance with genotyping. Portions of these data were previously pre- tion. DRD4 VNTR was the single target of the current th sented at the 39 annual meeting of the Association for the Behavioral and study based on the existing literature [37,38,40] and the th Cognitive Therapies, Washington, DC, and the 28 annual meeting of the small sample size, however, other recent studies have sug- Research Society on Alcoholism, Santa Barbara, CA. This research was sup- gested provocative interactions with other alleles. 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Publish with Bio Med Central and every 81. Myrick H, Anton RF, Li X, Henderson S, Drobes D, Voronin K, scientist can read your work free of charge George MS: Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving. Neuropsy- "BioMed Central will be the most significant development for chopharmacology 2004, 29:393-402. disseminating the results of biomedical researc h in our lifetime." 82. Tapert SF, Brown GG, Baratta MV, Brown SA: fMRI BOLD Sir Paul Nurse, Cancer Research UK response to alcohol stimuli in alcohol dependent young women. Addict Behav 2004, 29:33-50. Your research papers will be: 83. Tapert SF, Cheung EH, Brown GG, Frank LR, Paulus MP, Schweins- available free of charge to the entire biomedical community burg AD, Meloy MJ, Brown SA: Neural response to alcohol stim- uli in adolescents with alcohol use disorder. 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