Ebstein1 first highlighted the saga of an ‘adventure gene’: the dopamine D4 receptor gene (DRD4) and its association with substance abuse and personality. This was followed with a report by Baron2 who suggested that this saga is sagging due to conflicting reports emerging. It now appears that the saga continues with ‘severity of dependence’ to substance abuse, another variable that may be pertinent to the DRD4 association.3
In 1996, Ebstein and colleagues4 examined DRD4 and its association with the human personality trait Novelty Seeking (NS) in a sample of healthy volunteers recruited from an unrelated. Israeli staff/student population. Using Cloninger's Tridimensional Personality Questionnaire (TPQ)5 to measure NS (high novelty seekers are characterized by their impulsive and exploratory behaviour), they reported an association between the DRD4 gene and normal human personality. They analyzed TPQ scores and frequency of DRD4 exon III repeat polymorphisms in 124 samples and found that subjects with the seven-repeat allele exhibited significantly higher NS scores when compared to subjects lacking the seven-repeat allele. This association did not appear to be due to population stratification as it was independent of ethnicity, age or sex of the subjects (69 men, 55 women, mean age 29.8 years).
Benjamin et al6 provided support for this initial study by investigating the relationship between the DRD4 exon III sequence variant and personality test scores amongst a sample of 315 American family members and individuals. The study confirmed initial findings of the Ebstein et al study4 despite methodological differences. For example. Benjamin et al used a sample of white Americans, of whom 95% were male. In addition, they employed Eysenck's NEO-PI-R, which is based upon a trait model of personality, with NS falling in the extraversion factor. This is in contrast to the TPQ, which is based on a biological model in which three independent dimensions of temperament are attributed to genetically and neurochemically distinct pathways, with novelty seeking being mediated by dopamine neurotransmission.1 Finally, Benjamin et al6 did not examine presence or absence of the seven-repeat allele, but grouped individual genotypes into long or short alleles on the gene. Subjects with the long alleles were found to be significantly higher novelty seekers than those with the short alleles.
A third study, conducted by Ebstein,1 offered additional evidence for the association with DRD4 and NS, using similar methods to their previous study. In the same year, Ono and colleagues7 conducted a similar study with 153 normal, Japanese women (mean age 18.7 years). They used the TPQ to measure NS and found an association with long alleles at the polymorphic exon III repeats sequence of DRD4 and NS.
Evidence continued to build for the association between DRD4 and NS amongst healthy people with different ethnic origins. To date, a further six studies8,9,10,11,12,13 have been published, making a total of ten studies offering support for this association. One study used a sample of 119, twelve-year-old Caucasian boys,8 there have been two Japanese studies,10,12 a Finnish study,9 an Israeli study13 and a German study11 conducted.
Despite substantial evidence emerging for the association between the DRD4 gene variant and NS, there have been conflicting reports showing a lack of association between these variables,14,15,16,17,18,19,20,21,22,23 which may be attributable to basic methodological differences between studies. Ebstein1 established guidelines for conducting such research and in doing so highlighted the controversy surrounding this association. Baron2 swiftly responded by offering constructive criticism concerning methodological issues surrounding this research, questioning whether the saga of the ‘adventure gene’ was sagging.
Research refuting the association with DRD4 and NS began in 199614 and was shortly followed by three articles in 1997,18,19,20 four articles in 199815,16,17,23 and two in 1999.21,22 There are several possible reasons as to why these studies failed to find an association with DRD4 and NS. Firstly, age is an important variable to consider in personality research. NS diminishes with age so to obtain consistent personality scores, subjects should be young (ideally under the age of 45 years).24 Reports providing evidence for the association with DRD4 and NS used subjects between the ages of 12–35 years.1,4,6,7,8,9,10,11,12,13 The subjects used in studies that failed to find a significant association with DRD4 and NS were older, between 18–62 years.14,15,16,17,18,19,20,21,22,23 Of these studies reporting negative findings, 60% employed subjects who were over the age of 35 years.17,18,19,20,22,23 It appears that negative results may have been obtained because NS levels were lower in these people because they were older.
Secondly, failure to find an association with DRD4 and NS may be due to the lack of uniformity employed when measuring the personality trait. Scales with high retest reliability and valid for use with a variety of populations and cultures should be used for this research.1 The TPQ Novelty Seeking scale and the ZKPQ Sensation Seeking Scale are suitable and moderately correlated allowing results to be generalized across different studies.3 Failure to find associations with DRD4 and personality traits may be due to authors using different personality scales to measure NS.
Another factor that may be pertinent to the association is ethnicity. So far, studies have used Israeli, Japanese, American, Swedish, Finnish and German populations. The association may be dependent upon ethnicity as genetic variants vary across different ethnic groups. It is possible that the relationship between DRD4 and NS is real, but only in some populations and not others.
Gender is another variable to be considered in light of these conflicting findings. Mixed gender groups of sufficient size should be used for this research. For example, the Japanese replication study observing an association was restricted to women.7 Whereas the Finnish study which did not observe a significant association with DRD4 and NS only included men.14 This controversy may have been due to different gender groups being used in each study.
While the search for a true association with DRD4 and NS continues, the search for genes associated with substance abuse is taking the same theme. Similar conflicting findings are also reported in substance abuse with half of the studies reporting a significant association with the DRD4 gene variant25,26,27,28,29,30 whilst the other half have failed to replicate this association.31,32,33,34,35,36,37,38
The pattern that is emerging is that significant associations between DRD4 and substance abuse are found amongst samples of drug abusers (heroin and nicotine dependence)26,27,29 and non-significant results are yielded from samples of alcohol abusers.31,32,34,35,36,37,38 One study did find a significant association with DRD4 and alcohol abuse but this was only observed in alcohol abusers who were distinguished by the ALDH2 polymorphism.28 ALDH22 (as opposed to ALDH21) is an allele whose presence causes a flushing reaction following alcohol ingestion which therefore acts protectively to lower the incidence of alcoholism in people with this genotype.
Furthermore, diagnosing substance abuse may be another important factor that may influence the results obtained from these association studies. If substance abuse or dependence status is not clearly defined amongst the sample or controls then associations between variables may not be found due to the substance abuse group being too similar to the control group. This issue gives rise to the continuation of the saga with the association between DRD4, substance abuse and NS. A recent study3 measured severity of dependence and failed to support previous findings of a significant association with DRD4 and substance abuse. However, results did suggest that possession of the long-repeat genotype at the DRD4 receptor makes an individual more susceptible to severe dependence upon a substance. This study indicated that substance-dependent subjects who possess the long-repeat genotype rate their severity of dependence significantly higher than those with the short-repeat genotype. It was concluded from this study that the variant at DRD4 does not increase susceptibility to dependence per se, but that the variant may partially determine severity of dependence.3 The lack of association previously reported might have occurred because dependence severity was not analyzed in association with genotype.
To highlight the importance of dependence severity in association studies another study has since reported an association between pathological gambling and the Monamine Oxidase gene (MAOA) polymorphism.39 The study found no significant differences between pathological gamblers and healthy controls in overall allele distribution at the MAOA gene but when severity of gambling was considered they did find a significant association between allele distribution in a subgroup of severe gamblers.
By reviewing this recent research, it can be concluded that there may be an association with DRD4 and NS amongst severe drug-dependent populations. Therefore, the DRD4 gene may not predispose individuals to addiction per se, but having the genetic variant may predispose substance abusers to a severe dependency. Therefore, does the saga continue for the DRD4 gene and its association with NS and substance abuse? As with all sagas we shall have to wait for further developments. Resolution of the saga will depend on methodologically stringent studies. Furthermore, studies may need to account for severity of dependence, another variable that may be important to this association before we can witness the outcome of this saga.
Ebstein RP . Saga of an adventure gene: novelty seeking, substance abuse and the dopamine D4 receptor exon III repeat polymorphism Mol Psychiatry 1997 2: 381–384
Baron M . Mapping genes in personality: is the saga sagging? Mol Psychiatry 1998 3: 106–108
Lusher J, Ebersole L, Ball D . Dopamine D4 receptor gene and severity of dependence Addict Biol 2000 5: 471–474
Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D et al. Dopamine D4 receptor (DRD4) exon III polymorphism associated with the human personality trait of novelty seeking Nature Genet 1996 12: 78–80
Cloninger CR . Tridimensional Personality Questionnaire Version 4 Washington University Press: St Louis 1987
Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH . Population and familial association between the D4 dopamine receptor gene and measures of novelty seeking Nature Genet 1996 12: 81–84
Ono Y, Manki H, Yoshimura K et al. Association between dopamine D4 receptor exon II polymorphism and novelty seeking in Japanese subjects Am J Med Genet 1997 74: 501–503
Noble EP, Ozkaragoz T, Ritchie TL, Zhang X, Belin TR, Sparkes RS . D2 and D4 dopamine receptor polymorphisms and personality Am J Med Genet 1998 81: 257–267
Ekelund J, Lichtermann D, Jarvelin MR, Peltonen L . Association between novelty seeking and the type 4 dopamine receptor gene in a large Finnish cohort sample Am J Psychiatry 1999 156: 1453–1455
Tomitaka M, Tomitaka SI, Otuka Y, Kim K, Matuki H, Sakamoto K et al. Association between novelty seeking and dopamine receptor D4 exon III polymorphism in Japanese subjects Am J Med Genet 1999 88: 469–471
Strobel A, Wehr A, Michel A, Brocke B . Association between the dopamine D4 receptor (DRD4) exon III polymorphism and measures of novelty seeking in a German population Mol Psychiatry 1999 4: 378–384
Okuyama Y, Ishiguro H, Nankai M, Shibuya H, Watanabe A, Arinami T . Identification of a polymorphism in the promoter region of DRD4 associated with the human novelty seeking personality trait Mol Psychiatry 2000 5: 64–69
Benjamin J, Osher Y, Kotler M, Gritsenko I, Nemanov L, Belmaker RH et al. Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransfarese (COMT) Mol Psychiatry 2000 5: 96–100
Malhotra AK, Virkkunen M, Rooney W, Eggert M, Linnoila M, Goldman D . The association between dopamine (D4DR) 16 amino acid repeat and novelty seeking Mol Psychiatry 1996 1: 388–391
Pogue-Geile M, Deka R, Debski T, Manuck S . Human novelty-seeking personality traits and dopamine D4 receptor polymorphisms: a twin and genetic association study Am J Med Genet 1998 81: 44–48
Benjamin J, Osher Y, Belmaker RH, Ebstein RP . No significant associations between two dopamine receptor polymorphisms and normal temperament Hum Psychopharmacol 1998 13: 11–15
Jonsson EG, Nothen MM, Gustavsson JP, Neidt H, Forslund K, Evenden M et al. Lack of association between dopamine D4 receptor gene and personality traits Psychol Med 1998 28: 985–989
Gelernter J, Kranzler H, Coccaro E, Siever L, New A, Mulgrew CL . D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance dependent, personality disorder and control subjects Am J Hum Genet 1997 61: 1144–1152
Jonsson EG, Nothen MM, Gustavsson JP, Neidt H, Brene S, Tylec A et al. Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene polymorphisms Am J Psychiatry 1997 154: 697–699
Vandebergh DJ, Zonderman AB, Wang J, Uhl GR, Costa PT . No association between novelty seeking and dopamine receptor (D4DR) exon III seven repeat alleles in Baltimore longitudinal study of ageing participants Mol Psychiatry 1997 2: 417–419
Kuhn K, Meyer K, Nothen M, Gansicke M, Papassotiropoulos A, Maier W . Allelic variants of dopamine receptor D4 and serotonin receptor 5HT2c and temperatment factors: replication tests Am J Med Genet 1999 88: 168–172
Bau CHD, Roman T, Almeida S, Hutz MH . Dopamine D4 receptor gene and personality dimensions in Brazilian male alcoholics Psychiatr Genet 1999 9: 139–143
Sullivan PF, Fifield WJ, Kennedy MA, Mulder RT, Sellman JD, Joyce PR . No association between novelty seeking and the type 4 dopamine receptor gene (DRD4) in two New Zealand samples Am J Psychiatry 1997 155: 98–101
Zuckerman M . Sensation Seeking: Beyond the Optimal Level of Arousal Lawrence Erlbaum: NJ
Perez de Castro I, Ibanez A, Torres P, Saiz-Ruiz J, Fernandez-Piqueras J . Genetic association study between pathological gambling and a functional DNA polymorphism at the D4 receptor gene Pharmacogenetics 1997 7: 345–348
Shields PG, Lerman C, Audrain J, Bowman ED, Main D, Boyd NR et al. Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians Cancer, Epidemiol Biomark Prevent 1998 7: 453–458
Kotler M, Cohen H, Segman R, Gritsenko I, Nemanov L, Lerer B et al. Excess dopamine D4 receptor (DRD4) exon III seven repeat allele in opioid dependent subjects Mol Psychiatry 1997 2: 251–254
Muramatsu T, Higuchi S, Murayama M, Matsushita S, Hayashida M . Association between alcoholism and the dopamine D receptor gene J Med Genet 1996 33: 113–115
Li T, Xu K, Deng H, Cai G, Liu J, Liu X et al. Hypervariable segment in the dopamine receptor D4 gene Hum Mol Genet 1993 2: 767–773
Comings DE, Gonzalez N, Wu S, Gade R, Muhleman D, Saucier G et al. Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviours Am J Med Genet 1999 88: 358–368
Sander T, Harms H, Dufeu P, Kuhn S . Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics Am J Med Genet 1997 74: 483–487
Roman T, Bau CHD, Almeida S, Hutz HM . Lack of association of the dopamine D4 receptor gene with alcoholism in a Brazilian population Addict Biol 1999 4: 203–207
Franke P, Nothen MM, Wang T, Knapp M, Lichtermann D, Neidt H et al. DRD4 exon III VNTR polymorphism—susceptibility factor for heroin dependence? Results of a case-control and a family based association approach Mol Psychiatry 2000 5: 101–104
Ishiguro H, Saito T, Shibuya H, Arinami T . Association study between genetic polymorphisms the 14–3–3 chain and dopamine D4 receptor genes and alcoholism Alcohol Clin Exp Res 2000 24: 343–347
Parsian A, Chakraverty S, Fisher L, Cloninger CR . No association between polymorphisms in the human dopamine D3 and D4 receptors genes and alcoholism Am J Med Genet 1997 74: 281–285
Geijer T, Jonsson E, Neiman J, Persson M, Brene S, Gyllander A et al. Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics J Clin Exp Res 1997 21: 35–39
Chang FM, Kidd KK . Rapid molecular haplotyping of the first exon of the dopamine D4 receptor gene by heteroduplex analysis Am J Med Genet 1997 74: 91–94
Adamson MD, Kennedy J, Petronis A, Dean M, Virkkunen M, Linnoila M et al. DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls Am J Med Genet 1995 60: 199–205
Ibanez A, Perez de Castro I, Fernandez-Piqueras J, Blanco C, Saiz-Ruiz J . Pathological gambling and DNA polymorphic markers at MAO-A and MAO-B genes Mol Psychiatry 2000 5: 105–109
About this article
Cite this article
Lusher, J., Chandler, C. & Ball, D. Dopamine D4 receptor gene (DRD4) is associated with Novelty Seeking (NS) and substance abuse: the saga continues . . .. Mol Psychiatry 6, 497–499 (2001). https://doi.org/10.1038/sj.mp.4000918
Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice
Translational Psychiatry (2021)
Dopamine-related receptors, substance dependence, behavioral problems and personality among juvenile delinquents
Personality and Individual Differences (2021)
Biological Psychiatry (2021)
Why are Women More Religious than Men? Do Risk Preferences and Genetic Risk Predispositions Explain the Gender Gap?
Journal for the Scientific Study of Religion (2020)
International Journal of Molecular Sciences (2019)