Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients☆
Introduction
Alcohol and drug misuse is estimated to cost $246 billion annually and is responsible for premature mortality, morbidity, crime, traffic accidents, and liver disease (Harwood et al., 1999). The etiology of substance dependence is not entirely clear, but heritability estimates suggest that genetic factors account for 40–80% of the variance associated with this diagnosis (e.g., Kendler et al., 2005, Enoch and Goldman, 2001), with cannabis potentially less heritable (41%) and tobacco the most heritable (79%) substance. Identification of the genes contributing to substance dependence would allow for treatment efforts to be targeted on a biological basis as well as allow for more thorough gene by environment analyses (Heath et al., 2002). To that end, genes in several biological systems have been investigated in relation to substance dependence (e.g., dopamine, serotonin, GABA, glutamate, etc.), albeit with mixed results.
Although it is possible that various genes may be differentially associated with the likelihood of developing alcohol versus other drug dependence (e.g., polymorphisms in the alcohol metabolizing enzymes may impact likelihood of alcohol dependence but not tobacco dependence), dopaminergic function underlies all drugs of abuse (Kalivas and Volkow, 2005). Accordingly, variation in dopaminergic genes may impact dependence rates across multiple substances.
In addition to examining genes in systems identified as central to dependency for many substances, use of carefully specified phenotypes is critical. For example, the diagnostic criteria for alcohol dependence do not distinguish between persons who begin to drink alcohol problematically for different reasons (e.g., modulation of negative affect for purposes of self-medication, reactivity to cues, or drinking to avoid withdrawal). This heterogeneity may result in poorly specified phenotypic data and may account for inconsistency in results of studies designed to associate specific genes to alcohol dependence. For example, a gene variant that predicts ability to manage negative affect may influence risk for developing alcohol dependence, but this relationship might be obscured in a study of alcohol dependent persons with multiple etiologies. The use of intermediate phenotypes on the pathway between genes and diagnosis is an approach that allows far greater power to identify specific genetic risk and protective factors (Gottesman and Gould, 2003). Useful intermediate phenotypes range from those proximal to gene effects to the more distal measures of behavior associated with alcohol dependence.
Although cellular research on the potential functional consequences of the VNTR polymorphism of the dopamine D4 receptor gene (DRD4) has yielded mixed results (e.g., some evidence for functional differences in 7 repeat receptors compared with 2 or 4-repeat receptors (Asghari et al., 1995) and some evidence suggesting differences between the 2-repeat and the 4 and 7 repeat receptors (Czermak et al., 2006)), clinical research across multiple intermediate phenotypes and substances suggest a consistent pattern of results. Functional neuroimaging of recently detoxified alcoholics suggests that participants who carry the 7 or more repeats in the DRD4 VNTR (DRD4L) show increased activation to alcohol-related stimuli in the anterior cingulate and associated prefrontal cortical areas compared with participants who carry only shorter variants (DRD4S) (Smolka et al., 2005, manuscript under review). Laboratory studies of reactivity to associated cues have shown greater subjective urges reported by DRD4L participants compared to DRD4S participants in smoking and alcohol studies (Hutchison et al., 2002a, Hutchison et al., 2002b, McGeary et al., 2001), a study of heroin addicts (Shao et al., 2006), and even a study related to food craving (Sobik et al., 2005). Pharmacogenetic studies suggest the differential subjective urge for alcohol may be attenuated by a D4 receptor antagonist relative to active placebo (Hutchison et al., 2003). A behavior economics study found that DRD4L participants valued alcohol more highly than DRD4S participants (Mackillop et al., under review). Finally, the examination of urges in the natural environment through the use of palm-top computers suggests that DRD4L carriers report greater urges to drink alcohol than DRD4S participants (McGeary et al., 2004, Monti et al., 2004).
Although this pattern of results across multiple studies suggest that the DRD4 VNTR polymorphism is consistently related to urge phenomenology across substances of abuse, it is not clear if the long variant is associated with an underlying liability to greater desire or if the DRD4 gene moderates the neuroadaptive changes that occur with extended use. A direct test of these possibilities is difficult as it requires either administering drugs or alcohol to adolescents prior to their becoming regular users (presenting obvious ethical problems) or attempting to assess responses to drug or alcohol use early in the experimentation stage. The cue reactivity studies described above cannot inform this question due to their reliance on associative learning over repeated exposures.
Despite these ethical and practical difficulties, examination of the DRD4 VNTR polymorphism in adolescents may have utility. Although adolescents may have a history of alcohol and other drug use, it is likely that this history will be shorter than the histories of the participants in the studies described above. Positive associations of the DRD4 gene and alcohol and drug use behaviors would suggest that either relatively shorter consumption histories still manifest the expected differences or that indeed the DRD4 VNTR is related to some underlying vulnerability. Moreover, positive results might suggest the possibility of matching pharmacological treatments to genetic background as has been suggested in the adult literature (Oslin et al., 2003). Previous research has demonstrated the potential utility of naltrexone in teens (Deas et al., 2005) but has not examined potential genetic moderators. Accordingly, in this study we examine a subset of adolescents from a larger assessment study that characterizes alcohol and drug use in a sample of youth at high risk for the development of alcohol and drug dependence, seriously mentally ill adolescents hospitalized on a psychiatric inpatient unit.
Section snippets
Participants
One hundred and one adolescents hospitalized on an acute adolescent psychiatric inpatient unit and their parents/guardians were asked to participate in this study on a voluntary basis. The large majority of adolescents were hospitalized due to suicidal thoughts or behavior. Adolescents were recruited from the major child psychiatric hospital in the state which accepts Medicaid, uninsured, and privately insured youth. Of those approached for participation, 77 (76%) were successfully recruited.
Discussion
The first aim of this study was to investigate whether the DRD4 VNTR polymorphism was associated with substance use behavior in a group of seriously mentally ill adolescents. The second aim was to examine the relationship of this polymorphism with single items and subscales thought to be related to the intermediate phenotype of urge for use of substances. Despite low power to detect effects and a psychiatrically heterogeneous sample, two findings were of significance. The first finding was that
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Research supported by a grant from the National Institute of Mental Health (NIMH) 5R01MH065885-03 (CES), a Research Career Development Award and Senior Research Career Scientist Award from the Medical Research Service of the Department of Veterans Affairs (JEM and PMM).