The DRD4 VNTR Polymorphism Influences Reactivity to Smoking Cues Kent E. Hutchison and Heather LaChance University of Colorado at Boulder Raymond Niaura Miriam Hospital and Brown University Angela Bryan and Andrew Smolen University of Colorado at Boulder Recent research has indicated that craving for tobacco can be reliably elicited by exposure to smoking cues, suggesting that cue-elicited craving for tobacco may be a useful phenotype for research on genetic factors related to nicotine dependence. Given the potential role of dopamine in cue-elicited craving, the authors examined whether the DRD4 VNTR polymorphism is associated with cue-elicited craving for tobacco. Participants who were homozygous or heterozygous for the 7 repeat (or longer) allele were classified as DRD4 L, and all other participants were classified as DRD4 S. Participants were exposed to smoking cues before smoking either high-nicotine cigarettes or control cigarettes. Analyses suggested that participants in the L group demonstrated significantly greater craving, more arousal, less positive affect, and more attention to the smoking cues than did the participants in the S group. The role of genetics in behavioral research will continue to grow significantly in the near future, as behavioral scientists find that genetic information has become increasingly inexpensive and easy to collect (Plomin & Crabbe, 2000). As important genetic factors are identified, the focus of research will shift from identifying genetic factors to describing how these specific factors influence behavior; this shift should have a significant impact on how scientists approach behavioral research (Plomin & Crabbe, 2000). For example, genetic factors in smoking behavior were first noted by Fisher (1958), and scientists have since demonstrated that genetic factors account for approximately 46 – 84% of the variance in the initiation of smoking behavior (e.g., Carmelli, Swan, Robi- nette, & Fabsitz, 1992; Heath & Madden, 1995; Stallings Hewitt, Beresford, Heath, & Eaves, 1999) and 39 – 49% of the variance in the persistence of smoking behavior (e.g., Madden et al., 1999). However, the specific genetic factors that influence smoking be- havior still need to be identified, and a model to explain how these factors are mechanistically related to smoking behavior needs to be developed. Smoking behavior is a major target of behavioral science because of its impact on mortality and morbidity; identi- fication of the specific genetic mechanisms that underlie smoking behavior can be expected to lead to a more refined understanding of the etiology and treatment of nicotine dependence. In response to the inherent difficulty of identifying genetic factors that contribute to behavior phenotypes that are often amor- phous, scientists have recently recommended a different approach to genetic research that emphasizes the identification of highly specific behavioral phenotypes, or endophenotypes, that can sub- sequently be tested for association with a particular genetic factor (Burmeister, 1999; Farren et al., 1999; Hill & Neiswanger, 1997; Leboyer et al., 1998; Malhotra & Goldman, 1999; Schuckit, 1999). The expectation is that this approach should greatly facilitate research on the genetic causes of behavior. To some extent, re- search on nicotine dependence has already moved in this direction, as other researchers have noted the need for a more systematic and detailed approach to phenotypic description (Pomerleau & Kardia, 1999; Swan, 1999). In terms of identifying genetic factors and the mechanisms by which they influence smoking behavior, an ideal smoking endophenotype would be one that is narrowly defined, readily identifiable, empirically related to the clinical manifesta- tion of nicotine dependence, and associated with an underlying biological mechanism. Note that this type of endophenotype al- lows for increased statistical power to detect significant associa- tions with particular candidate genes and facilitates the interpre- tation of the findings. With respect to smoking, cue-elicited craving for tobacco rep- resents a potentially powerful endophenotype for research on genetic factors related to nicotine dependence. Although there has been some controversy over the definition of craving and its clinical relevance (see Sayette et al., 2000; Tiffany, 1990), numer- ous studies have indicated that exposure to smoking cues (e.g., the sight and smell of a lit cigarette) markedly increases craving for tobacco (see Carter & Tiffany, 1999; Hutchison, Niaura, & Swift, 1999; Niaura et al., 1988, 1998; Tiffany, Carter, & Singleton, 2000). In addition, cue-elicited craving for tobacco appears to have Kent E. Hutchison, Heather LaChance, and Angela Bryan, Department of Psychology, University of Colorado at Boulder; Raymond Niaura, Center for Preventive and Behavioral Medicine, Miriam Hospital, Provi- dence, Rhode Island, and Brown University; Andrew Smolen, Institute for Behavioral Genetics, University of Colorado at Boulder. We gratefully acknowledge the assistance of Rae Hicks and Angela Wooden. This research was supported by a grant from the National Cancer Institute (1R21CA81637) to Kent E. Hutchison. Correspondence concerning this article should be addressed to Kent E. Hutchison, University of Colorado, Department of Psychology, Muenz- inger Psychology Building, Campus Box 345, Boulder, Colorado 80309- 0345. E-mail: KentH@psych.colorado.edu Journal of Abnormal Psychology Copyright 2002 by the American Psychological Association, Inc. 2002, Vol. 111, No. 1, 134 –143 0021-843X/02/$5.00 DOI: 10.1037//0021-843X.111.1.134 134