Pathol Biol 2001 ; 49 : 710-7

 2001 Éditions scientifiques et médicales Elsevier SAS. Tous droits réservés

S0369-8114(01)00236-X/FLA
Original article

The genetics of addiction: alcohol-dependence and D3

dopamine receptor gene
P. Gorwood 1,2∗ , F. Limosin 1 , P. Batel 3 , E. Duaux 4 , L. Gouya 5 , J. Adès 1,2
1 Hôpital Louis Mourier, service de psychiatrie adultes, 178, rue des Renouillers, 92700 Colombes, France ;
2 unité CNRS UMR 7593-Paris VII, hôpital de la Salpêtrière, 47, boulevard de l’Hôpital, 75013 Paris, France ;
3 unité de traitement ambulatoire des malades alcooliques, hôpital Beaujon, 100, boulevard du Général Leclerc,
92110 Clichy, France ; 4 SHU Sainte-Anne, service de psychiatrie adultes, rue Cabanis, 75674, Paris cedex 14,
France ; 5 laboratoire de biochimie, fédération de biologie moléculaire, INSERM unité 409, France

(Received 10 July 2000; accepted 9 November 2000)

Summary
Alcohol-dependence is a complex phenotype, with behavioral, psychological, pharmacological, medical and
social dimensions. Aggregation studies, adoption and twin researches have demonstrated that the vulnerability
to alcohol-dependence is at least in part linked to genetic factors, the genetic vulnerability to alcoholism
being mainly not substance-specific. There are numerous candidate genes, but the D3 dopamine receptor is
specifically located in the limbic area, and in particular in the nucleus accumbens, which are involved in reward
and reinforcement behavior. Furthermore, a previous collaborative study showed that homozygosity for the BalI
DRD3 locus was more frequently observed in opiate dependent patients with high sensation seeking scores.
In this study, we analyzed the distribution of BalI DRD3 polymorphism in a new sample of 131 French male
alcoholic-patients (DSM III-R criteria) and 68 healthy controls matched for sex and origins. Although we replicated
the higher sensation seeking score in alcohol-dependent patients with comorbid dependence, we found no
significant difference in the DRD3 gene polymorphism between controls and alcoholic patients, regardless of
sensation seeking score, addictive or psychiatric comorbidity, alcoholism typology, and clinical specificities of
alcoholism. There is good evidence that gene coding for the dopamine receptor D3 does not play a major role in
the genetic vulnerability to alcoholism.  2001 Éditions scientifiques et médicales Elsevier SAS

addiction / alcoholism / dependence / dopamine / D3 receptor / genetics / impulsivity / sensation seeking

Résumé – L’addiction génétique : l’alcoolo-dépendance et le gène récepteur dopaminergique D3.

L’alcoolo-dépendance est une pathologie complexe et multifactorielle, incluant des dimensions comporte-
mentales, psychologiques, pharmacologiques, médicales et sociologiques. Les études d’agrégation familiale,
d’adoption et de jumeaux ont permis de démontrer que l’alcoolo-dépendance était en partie liée à des facteurs
de vulnérabilité génétique, ces facteurs étant peu spécifiques, mais vraisemblablement partagés avec les autres
dépendances. Il existe de nombreux gènes candidats, mais le gène codant pour le récepteur dopaminergique
D3 (RDD3) a l’intérêt spécifique d’être localisé préférentiellement dans les aires limbiques, et plus particuliè-
rement dans le noyau accumbens, structure anatomique impliquée dans les comportements de récompense
et de renforcement. De plus, une première étude d’association a montré que l’homozygotie pour le polymor-
phisme BalI du RDD3 était plus fréquemment retrouvée dans un groupe de sujets dépendants de l’héroïne et
ayant un score élevé de « recherche de sensation ». Dans cette étude, nous avons comparé la distribution des
polymorphismes du RDD3 dans un échantillon de 131 hommes français souffrant d’alcoolo-dépendance (selon
les critères DSM III-R) par rapport à 68 sujets sains, appariés pour l’âge et les origines ethniques. Bien que
nous confirmions les scores de recherche de sensation plus élevés chez les sujets souffrant de dépendance
comorbide, aucune association significative n’est mise en évidence entre les polymorphisme génétiques BalI

∗ Correspondence and reprints.

E-mail address: philip.gorwood@lmr.ap-hop-paris.fr (P. Gorwood).
 The genetics of addiction 711

du RDD3 et l’alcoolo-dépendance, même en prenant en considération le score de recherche de sensation, les

comorbidités addictives ou psychiatriques, la typologie de l’alcoolisme proposée par Cloninger, et différentes
spécificités cliniques de l’alcoolo-dépendance. Il est donc peu vraisemblable que gène codant pour le RDD3
ait un rôle majeur dans l’alcoolo-dépendance, au moins pour cet échantillon.  2001 Éditions scientifiques et
médicales Elsevier SAS

addiction / alcoolisme / dépendance / dopamine / génétique / impulsivité / récepteur D3 / recherche de sensation

Alcoholism aggregates in families, with the risk for al-
coholism in relatives of alcoholics being three to five
times higher than the risk in the general population [1].
Studies of half-siblings [2], twins and adoptees (for re-
view, see [3]), have shown that the familial component
of alcoholism is, at least in part, due to genetic lia-
bility. Finding the genes involved in the vulnerability
to alcohol dependence is counteracted by the relative
absence of knowledge of what is inherited, i.e. the bound-
aries of the phenotype. One preliminary evidence is the
existence of a large comorbidity between the different
dependencies. In the Epidemiological Catchment Area
study, the risk of drug dependence is six-times increased
in alcohol-dependent subjects, and the risk for alcohol-
dependence is four-times increased in the population of
drug-dependent patients [4]. This high comorbidity is
potentially explained by various etiological factors. An-
imal studies may help to highlight the respective role of
genetic and environment in the vulnerability to specific
substances. Animal studies showed that rat or mice in-
bred strains (genetically identical) have various responses
to substance abuse paradigm, partly because of genetic di-
versity [5]. Mice that do not develop high consumption of
alcohol, whatever the reinforcement process associated,
tend to develop no abuse of opiates and cocaine (F344
rats and DBA/2J mice). On the other hand, mice and rats
that have tendency to consume a large amount of alco-
hol (“alcohol preferring strains”), show the same pattern
of consumption for other drugs such as opiates, ampheta-
mines and cocaine [6, 7] (Lew rats and C57BL/6J mice).
These animal models show that what is inherited may
be more largely based on a core phenomenon such as
addiction or dependence, rather than alcoholism or any
dependence for a specific substance. Furthermore, recent
twin and familial studies showed that the genetic factors
involved in the risk for alcohol-dependence could con-
cern dependence without substance specificity, including
opiates and cocaine. A large familial study showed for
instance that the relatives of an affected proband with
dependence have an eight times increased risk for any de-
pendence [8]. The concept of familial cross-vulnerability
is reinforced by the convergent results of a twin study
[9] which shows that genetic factors are significantly in-
volved in the general vulnerability for dependence.
The candidate genes that may increase vulnerability
to dependence are not known, but a number of sub-
stances that share the potential for abuse by humans
also share the ability to enhance dopaminergic activity in
the mesolimbic-mesocortical circuits, considered as im-
portant for reward and reinforcement behavior [10 – 12].
Strains differing in their behavioral and neurochemical re-
sponses to acute amphetamine or cocaine challenge as
well as in their susceptibility to addiction were found
to have differences in DA receptors, characteristics wich
correlated with the behavioral differences between strains
[13]. Thus, many investigators have ascertained the role
of the first dopamine receptor gene, which had an avai-
lable and informative marker: a TaqI polymorphism of
the D2 dopamine receptor (DRD2) gene. Meta-analysis
of these association studies has shown an increased rela-
tive risk for alcoholism when a subject has the A1 allele of
the DRD2 gene [14]. However, a significant heterogeneity
was found between samples, which was primarily due to
the severity of alcoholism and the nature of the control
groups used. It is thus important to look for polymor-
phism of other dopamine receptors potentially involved
in alcoholism.
The D3 dopamine receptor (DRD3) gene is a candidate
gene for alcoholism for two main reasons. In compari-
son to the DRD2, which is expressed in all major brain
areas receiving dopaminergic projections, DRD3 is ex-
pressed in restricted limbic areas, namely the nucleus
accumbens and island of Calleja, areas which receive
dopaminergic inputs from the A10 cell groups [15].
Ethanol preferentially stimulates DA transmission in the
mesolimbic system, specifically in the nucleus accum-
bens [16]. Furthermore, animal experimentations have
shown that lesion of dopaminergic terminals in the nu-
cleus accumbens by the neurotoxin 6-hydroxydopamine
eliminates the self-administration of cocaine [17], sug-
gesting that dopaminergic neurons in the nucleus accum-
bens play a significant role in the motivation for the intake
of drugs such as cocaine, amphetamine or ethanol. Sec-
ondly, DRD3 mRNA has been detected at the level of the
substantia nigra and the ventral tegmental area, suggest-
ing that these receptors function also as autoreceptors [15,
18]. Dopamine autoreceptors inhibit dopamine synthesis,
dopamine release and electrical activity of dopaminer-
gic neurons, mechanisms that are presumably involved in
behavioral responses (such as inhibition of locomotor ac-
tivity) to small doses of agonists. A specific role of DRD3
in exploratory locomotion was established by the use of
DRD3 knock-out mice [19] and DRD3 selective antago-
nists [20, 21]. DRD3 could thus play a more specific role
712 P. Gorwood et al.

in the reward process involved in alcoholism and other Table I. Psychiatric, Personality and Addictive comorbidity in a French
dependencies. DRD3 has been cloned and localized on sample of 131 alcohol-dependent patients.
the 3q13.3 chromosome [18, 22, 23]. A point mutation Comorbid disorder N %
was detected in the coding part of the gene that creates a
Major depressive disorder 30 22.9%
BalI restriction enzyme site and leads to a substitution of
a Serine by a Glycine residue. This mutation is transmit- Pathological gambling 20 15.3%
ted according to codominant Mendelian law [24]. Agoraphobia 14 10.7%
We previously found that DRD3 polymorphism was Panic disorder 12 9.2%
not associated in three independent samples of alcohol-
Dysthymia 7 5.3%
dependent patients [25], but concluded that “more in-
formation should have been considered such as other Obsessive-Compulsive Disorder 2 1.5%
addictions and the Cloninger type of alcoholism”. Fur- Antisocial Personality Disorder 22 16.8%
thermore, we published a positive association between Opiate dependence 13 9.9%
opiate-dependent patients with high sensation-seeking Haschich dependence 13 9.9%
score, showing that the DRD3 gene may be involved in a
subsample of addictive patients [26] with high sensation- Sedatives dependence 12 9.2%
seeking score (above 24 on the Zuckerman scale). In the Cocaine dependence 6 4.9%
present study, we undertook an association study to test Amphetamine dependence 3 2.3%
the role of the DRD3 polymorphism in the mechanisms
underlying genetic vulnerability to alcoholism, taking
into account the existence of potential heterogeneity, thus (on the basis of all available clinical and familial data)
analyzing different sub-samples according to comorbidity was performed by two clinicians (P.B. and P.G.) blind
and psychological dimensions such as sensation seeking. for the results of the genotyping. The analyses were
As compensation for the genetic heterogeneity that has restricted to the patients for whom the classification
been strongly suspected for alcoholism is required, we could be made with enough reliability, as Cloninger
investigated a new sample of French male alcoholics with typology is not based on operational criteria. Thirty-
extensive data concerning different clinical specificities. four cases were rated as type I alcoholism and 18 cases
In this perspective, we collected information in order to as type II with sufficient validity according to the two
establish subgroups of alcoholism, based on age at onset clinicians. Lifetime psychiatric and addictive comorbidity
(early versus late), existence of familial history (familial were present in the sample, and are detailed in table I.
versus sporadic), comorbid antisocial personality disorder Only four patients had never smoked cigarettes in their
and other psychiatric comorbidity, and scores of sensation life, 15 patients were ex-smokers and the Fagerström
seeking. As Cloninger [27] distinguished type I and average score of tobacco dependence was 6.85. The
type II alcoholism, the former being potentially more average global sensation seeking score was 17.21 (s.d. =
dependent of genetic factors, we compared these two 8.55), with the different dimensions being dishinibition
groups. = 4.5 (s. d. = 2.4), thrill = 5.16 (s.d. = 3.1), experience
seeking = 4.5 (s.d. = 2.6) and boredom susceptibility 3.1
(s.d. = 2.46).
MATERIALS AND METHODS
Controls
Patients
Sixty-eight male control subjects were screened from
Analyses were based on a sample of male patients with a blood transfusion center for the following inclusion
French origins (for two generations) and alcohol de- criteria: French for at least two generations, without
pendence (N = 131). Lifetime psychiatric and addictive abuse or dependence (DSM III-R criteria [30]), and at
disorders were screened with a face-to-face interview en- least 35 years old. The age of 35 was considered as a
titled the Diagnostic Interview for Genetic Studies [28]. cut-off to reduce the risk that controls might be future
Sensation seeking was evaluated on a self-rating scale alcoholics. Only ten controls had at least one criteria of
[29]. alcohol-dependence, appearing on average at 32.6 years
The average age at interview of the patients was 43.6 old (standard deviation = 8.6).
years (standard deviation = 10.3). They began to drink Twelve controls fulfilled DSM III-R criteria for a major
alcohol regularly on average at 19.2 years (s.d. = 5.93), depressive disorder (17.6%), and the following diag-
showing their first symptom of alcohol-dependence on nostics were found in some (different) patients, namely
average 8.2 years later (s.d. = 7.4). The average MAST agoraphobia (N = 2), dysthymia (N = 1), pathological
(Michigan Alcohol Screening Test) score was 32.6 (s.d. gambling (N = 1), and obsessive-compulsive disorder
= 12.0). The contextual rating of Cloninger typology (N = 1). One control made a suicidal attempt (1.8%) dur-
 The genetics of addiction 713

Table II. BalI DRD3 genotype counts in 131 alcohol-dependent patients and 68 controls according to clinical specificities.
Population N Homozygosity Heterozygosity χ2 df p
Controls 68 31 37
Patients
All of them 131 64 67 0.19 1 0.66
Early onset 71 30 41
Late onset 49 26 23 1.36 1 0.24
Familial 25 16 9
Sporadic 62 25 37 4.01 1 0.04
Type I/II (contextual rating)
Type II 22 10 12
Type I 43 19 24 0.01 1 0.92
ASPD 21 11 10
No ASPD 95 45 54 0.33 1 0.56
Psychiatric comorbidity
Primary 108 53 55
Secondary 13 4 9 1.56 1 0.21

Complications (at least one symptom)

Withdrawal 78 36 42
None 27 12 15 0.02 1 0.88
Psychiatric 94 43 51
None 17 9 8 0.30 1 0.58
Somatic 96 47 49
None 35 17 18 0.00 1 0.97

Comorbid dependence
None 100 48 52
Any 21 9 12 0.18 1 0.67
Opiate 13 5 8 0.42 1 0.52
Cannabis 13 8 5 0.84 1 0.36
Sedatives 12 7 5 0.46 1 0.50
df = degree of freedom; type I and II (Cloninger typology); early onset = before 25 years; ASPD = antisocial personality disorders; Secondary
alcoholism = alcohol-dependence that occur after the onset of another psychiatric disorder.

ing a major depressive episode. The average MAST score
of controls was 1.3 (standard deviation = 3.5). The aver-
age global sensation seeking score was 17.13 (s.d. = 6.1),
with the different dimensions being dishinibition = 3.04
(s.d. = 2.0), thrill = 6.90 (s.d. = 2.8), experience seeking
= 5.22 (s.d. = 2.0) and boredom susceptibility = 1.97
(s.d. = 7).
Molecular genetic analysis
DNA was extracted from peripheral leukocytes. The
first exon of D3RG was amplifying by Polymerase
Chain Reaction (PCR) as previously described [24].
Briefly, the PCR was performed with the following
primers: 5 -GCT CTA TCT CCA ACT CTC ACA-
3 , and 5 -AAG TCT ACT CAC CTC CAG GTA-3 .
Target sequences were amplified in a 25 µL reaction
mixture containing 100 ng of genomic DNA in 50
mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl2 ,
5 pmol of each primer, 100 µM of each dNTP (dATP,
dCTP, dGTP, dTTP), 0.5 mM dithiothreitol, 0.15 µL
(1.5 µCi) 32 P dATP (Amersham), 0.01% gelatin and
1.5 units/sample of Taq polymerase (AmpliTaq, Perkin-
Elmer Cetus). The PCR involved initial denaturation at
94◦ C for six minutes, followed by 30 cycles of annealing
at 56◦ C for one minute, polymerization at 72◦ C for one
714 P. Gorwood et al.
minute, and denaturation at 92◦ C for one minute, with
a final extension step at 72◦ C for eight minutes. The
amplified DNA were then digested with the restriction
endonuclease BalI (MscI, New England Biolabs) in a
10 µL incubation volume. The digested fragments were
electrophoresed in 8% polyacrylamide at 1.2 kV for one
hour in a vertical sequence gel electrophoresis apparatus
(BRL). The gel was dried for 30 minutes in a slab gel
dryer (Savant Instruments Inc.) and autoradiographed
using X-omat film (Eastman Kodak Co.) in an X-Ray
cassette with intensifying screens at −80◦ C, overnight.
The DNAs from all individuals were examined at least
twice in separate experiments. The RFLP status was
assigned by two independent raters (PG, LG) who were
blind for the clinical status of the subjects.
Statistics
A chi-square test was used to compare genetic polymor-
phism in patients and controls within each sample. For
small samples (such as patients with comorbid disorders),
the odds-ratio (with a 95% confidence interval) was pre-
ferred to chi-square, the former reflecting less clearly the
strength of the association. Limitation of the analysis to
the patients who can be classified with enough validity in
the different subgroups explain why the sum of the pa-
tients are not systematically 131 in table I. As this study
is a tentative replication of a previous positive finding be-
tween homozygosity and a sub-group of addict patients,
the comparisons were restricted to homozygosity ver-
sus heterozygosity, in order to decrease the possibility of
chance finding according to multiple tests. Genotype fre-
quencies were compared with those expected according to
the Hardy-Weinberg equilibrium using also a chi-square
test (with one degree of freedom (df)). Differences in
averages were analyzed with an ANOVA test, when the
sample was large enough, and the non-parametric Mann-
Whitney test was once used for a sample with less than 20
subjects. Difference in variance (whatever the mean) was
analyzed with an F test. All statistics were performed on
SPSS® software.
RESULTS
Allelic distributions of the BalI RFLP of the DRD3 gene
were in accordance with the Hardy Weinberg expected
distribution, for the sample as a whole (χ 2 = 2.32, df = 1,
p = 0.13), for controls (χ 2 = 0.46, df = 1, p = 0.50) and
for patients (χ 2 = 1.93, df = 1, p = 0.16). The allelic dis-
tribution of the BalI DRD3 polymorphism was not found
significantly different between patients and controls, nei-
ther between subsamples of alcohol-dependent patients
considering different clinical traits, typology or comor-
bidity (table I). Familial alcoholism (having at least one
first-degree relative affected with alcohol dependence)
had a moderate but significant excess of homozygosity
for the BalI DRD3 gene compared to sporadic patients,
but there was no difference between familial alcohol-
dependent patients and controls (χ 2 = 2.48; df = 1; p =
0.12). Furthermore, the significance (p = 0.04) of the ex-
cess of homozygosity for the BalI DRD3 gene in familial
alcohol-dependent patients compared to sporadic was no
more positive if the Bonferonni correction was applied
(p = 0.05/13 tests = 0.004).
The sensation seeking score had the same pattern of
distribution in patients and controls, but with a larger vari-
ance for patients than controls, as appearing in figure 1,
and as the F test, comparing variances between two sam-
ples, demonstrated (F = 1.99; df = 108; p = 0.0019).
The difference in distribution of sensation score in the
two samples may be explained by an excess of patients
with high sensation-seeking score (over 24), as these pa-
tients were more frequently observed in patients than in
controls (χ 2 = 7.23; df = 1; p = 0.007).
The BalI DRD3 polymorphism did not play a major
role in the difference of distribution of sensation seek-
ing score in alcohol-dependent patients, as the average of
sensation seeking score was not significantly different be-
tween patients with or without homozygosity at this locus
(F1/104 = 0.105; p = 0.75). Furthermore, the frequency
of alcohol-dependent patients with high sensation seeking
score (above 24) was not significantly different in the two
groups according to homozygosity (19.6%) versus het-
erozygosity (32.6%) for the BalI DRD3 gene (χ 2 = 2.31,
df = 1, p = 0.13). The absence of relationship between
BalI DRD3 polymorphism and sensation-seeking score
was further confirmed in controls, as homozygosity for
the BalI DRD3 locus was not significantly increased in
controls subjects with a sensation-score above 24 (7 out
of 10) compared to controls with lower sensation-seeking
score (31 out of 59) (χ 2 = 1.05; df = 1; p = 0.30).
As some specific and undescribed dimensions of sensa-
tion-seeking may explain differences in the global score
that was observed in the previous study, we restricted the
analysis to the two dimensions that were significantly dif-
ferent between controls and alcohol-dependent patients,
namely dishinibition (F1/176 = 20.02; p < 0.0001) and
boredom susceptibility (F1/176 = 11.4; p = 0.0009).
Once more, The BalI DRD3 polymorphism did not play
a major role in the variance of these dimensions in
alcohol-dependent patients, as their averages were not
significantly different whether they were homozygous or
not at this locus for dishinibition (F1/107 = 0.008; p =
0.93) and for boredom susceptibility (F1/107 = 0.413;
p = 0.52).
Lastly, the previous differences in the allelic distrib-
ution of the BalI DRD3 polymorphism were found in
other dependencies than alcoholism. We thus reanalyzed
the distribution of sensation-seeking in the subsample
of alcohol-dependent patients with a comorbid depen-
dence (N = 19). The sensation-seeking score was closer
 The genetics of addiction
Figure 1. Distribution of sensation seeking score in controls and alcohol-dependent patients (as a whole or with another substance dependence).
to the one found in the study of opiate addicts (average =
23.05, sd = 7.8) and clearly deviated from the rest of this
sample (figure 1). Nevertheless, there was no difference
in BalI DRD3 polymorphism according to low versus
high sensation-seeking score in this population with co-
morbid dependencies. Homozygosity for the BalI DRD3
polymorphism was in fact slightly in excess in the low
sensation seeking score population (OR = 4.67; 95 %CI
[0.67–32.4]), contrary to the previous finding.
DISCUSSION
The observed genotype frequencies were in agreement
with the expected values according to the Hardy-Weinberg
equilibrium. No difference in the frequencies of the alle-
les of the BalI DRD3 polymorphism emerged between
controls and alcohol-dependent patients, neither for sub-
groups with clinical specificities (late versus early age of
onset, familial versus sporadic, type I versus type II al-
coholism, etc.) It could thus be concluded that in these
samples, BalI DRD3 polymorphism did not have an im-
portant role in the genesis of alcoholism, or in its related
features, as previously shown [25].
Although we observed an increased number of alcohol-
dependent patients (compared to controls) with a high
sensation-seeking score (above 24), we did not replicate
the previous findings on opiate addicts which showed that
the BalI DRD3 gene may be involved in a subgroup of
715
addict patients with high sensation-seeking score. This
negative finding may have different explanations.
Firstly, the average sensation-seeking score was not
different between alcohol-dependent patients and healthy
controls in our sample. Furthermore, the average of
sensation-seeking score between our 131 alcohol-depend-
ent patients (17 ± 9) and the 54 opiate addicts of the
previous study (26 ± 5) were significantly different (t =
8.6; df = 183; p < 0.0001). This is in accordance with the
fact that alcohol-dependent patients have lower sensation-
seeking scores than opiate addicts [31]. High sensation-
seeking scores has been regarded as a vulnerability factor
to drug use in the general population [32], but this may
not be equally relevant for alcohol-dependence. Alcohol
is widely available in our societies, and in particular
in France where this study was being performed. The
involvement of dopamine in drug seeking behavior may
thus be less important in the mechanism of alcohol-
dependence vulnerability.
Secondly, although the existence of common genes
involved in the vulnerability to dependence, whatever the
substance, is now generally admitted, recent aggregation
studies also showed that some (other) genes may be
involved in a more specific manner in different types of
dependence [33, 34], specifically for heroin dependence.
Tsuang et al. [9] pinpointed that heroin was the only
drug that did not share at least 60% of its total variance
with the common vulnerability to drug abuse, contrary
716 P. Gorwood et al.
to marijjuana, stimulants, sedatives and psychedelics.
Furthermore, heroin was the only drug that did not share
at least 20% of its genetic variance with the common
vulnerability to drug abuse. The existence of two previous
negative results on the BalI DRD3 polymorphism in
alcohol-dependent patients confirms that this genetic
polymorphism may not be involved in the vulnerability
to alcohol-dependence [25, 35].
Lastly, the negative results of our study may be ex-
plained by the choice of a case/control association study,
a design that has several limitations [36], or a lack of
power to detect a small and complex effect. On the other
hand our sample (N = 199) was larger than the previ-
ous positive study (N = 124). Thus, the possibility of
a chance finding explaining the previous positive result
has also been raised. The fact that our sub-population of
alcohol-dependent patients with comorbid hard-drug de-
pendence had a trend (p = 0.09) in the opposite direction
from the previous study is in favor of such a conclu-
sion, although these analyses are based on very small
sub-samples (N = 19).
In conclusion, the BalI DRD3 polymorphism, and the
homozygosity for this locus in particular, is not involved
in alcohol-dependent patients, whatever the psychiatric
and addictive comorbidity, and whatever the score of
sensation seeking. Although convergent data favor the
hypothesis that dopamine is involved in the vulnerability
to alcohol-dependence, this polymorphism (BalI) of this
gene (DRD3) does not seem to play a detectable role in
alcohol-dependence.
ACKNOWLEDGEMENTS
This work was promoted by INSERM (N◦ 339), with the
grants of INSERM (réseau 494001), AP (CRC-94038),
and IREB (9303-9718). We thank Pierre Sokoloff for his
technical assistance.
REFERENCES
1 Cotton NS. The familial incidence of alcoholism. J Stud Alcohol
1979; 40: 89-116.
2 Schuckit MA, Goodwin DA, Winokur GA. A study of alcoholism
in half-siblings. Am J Psychiatry 1972; 128: 1132-6.
3 Hesselbrock M. The genetic epidemiology of alcoholism. In:
Begleiter H, Kissin B, editors. The genetics of alcoholism. New
York, USA: Oxford University Press; 1995, p. 17-39.
4 Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mentale
disorders with alcohol and other drug abuse. Results from the
Epidemiologic Catchment Area (ECA) study. JAMA 1990; 264:
2511-8.
5 McClearn G, Rodgers D. Differences in alcohol preferences among
inbred stains of mice. Quaterly Journal on the Studies of Alcoholism
1959; 20: 681-95.
6 George F, Elmer G, Meisch R, Goldberg S. Orally delivered cocaine
functions as a positive reinforcer in C57BL/6J mice. Pharmacol
Biochem Behav 1991; 38: 897-903.
7 Berrettini W, Ferraro T, Alexander R, Buchberg A, Vogel W.
Quantitative trait loci mapping of three loci controlling morphine
preference using inbred mouse strains. Nature Genetics 1994; 7:
54-8.
8 Merikangas K, Stolar M, Stevens D, et al. Familial transmission of
substance use disorders. Arch Gen Psychiatry 1998; 55: 973-9.
9 Tsuang M, Lyons M, Meyer J, et al. Co-occurrence of abuse
in different drugs in men. The role of drug-specific and shared
vulnerabilities. Arch Gen Psychiatry 1998; 55: 967-72.
10 Lippa AS, Antelman SM, Fisher AE, Canfield RD. Neurochemical
mediation of reward: a significant role of dopamine? Pharmacol
Biochem Behav 1973; 1: 23-8.
11 Di Chiara G, Imperato A. Drugs abused by humans preferentially
increase synaptic dopamine concentrations in the mesolimbic sys-
tem of freely moving rats. Proc Natl Acad Sci USA 1988; 85:
5274-8.
12 Wise RA, Rompre PP. Brain dopamine and reward. Ann Rev
Psychol 1989; 40: 191-225.
13 Flores G, Wood GK, Barbeau D, Quirion R, Srivastava LK.
Lewis and Fischer rats: a comparison of dopamine transporter and
receptors levels. Brain Res 1998; 814: 1-2, 34-40.
14 Gorwood P, Adès J, Feingold J. Are genes coding for dopamine
receptors implicated in alcoholism?. Eur Psychiatry 1994; 9: 63-9.
15 Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B,
Schwartz JC. Localization of dopamine D3 receptor mRNA in the
rat brain using in situ hybridization histochemistry: comparison
with dopamine D2 receptor mRNA. Brain Res 1991; 564: 203-19.
16 Imperato A, Di Chiara G. Preferential stimulation of dopamine
release in the nucleus accumbens of freely moving rats by ethanol.
J Pharmacol Exp Ther 1986; 239: 219-28.
17 Roberts D, Koob GF, Klonoff P, Fibiger HC. Extinction and recov-
ery of cocaine self-administration following 6-hydroxydopamine
lesions of the nucleus accumbens. Pharmacol Biochem Behav 1980;
12: 781-7.
18 Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC.
Molecular cloning and characterization of a novel dopamine recep-
tor (D3) as a target for neuroleptics. Nature 1990; 347: 146-51.
19 Accili D, Fishburn C, Drago J, Steiner H, Lachowicz J, Park B, et
al. A targeted mutation of the D3 receptor gene is associated with
hyperactivity in mice. Proc Natl Acad Sci USA 1996; 93: 1945-9.
20 Sautel F, Griffon N, Sokoloff P, Schwartz JC, Launay C, Simon P,
et al. Nafadotride, a potent preferential dopamine D3 receptor
antagoonist, activates locomotion in rodents. J Pharmacol Exp Ther
1995; 275: 1239-46.
21 Waters N, Svensson K, Haadsma-Svensson S, Smith M, Carlsson A.
The dopamine D3 receptor: a post-synaptic receptor inhibitory on
rat locomotor activity. J Neural Transm (Gen Sect) 1993; 94: 11-9.
22 Giros B, Martres MP, Sokoloff P, Schwartz JC. Clonage du gène
du récepteur dopaminergique D3 humain et identification de son
chromosome. CR Acad Sci 1990; 311: 501-8.
23 Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, et
al. Chromosomal localization of the human D3 receptor gene. Hum
Genet 1991; 87: 618-20.
24 Lannfelt L, Sokoloff P, Martres MP, Pilon C, Giros B, Jönsson E, et
al. Amino-acid substitution in the dopamine D3 receptor as a useful
polymorphism for investigating psychiatric disorders. Psychiatr
Genet 1992; 2: 249-56.
25 Gorwood P, Martres MP, Adès J, et al. Lack of association
between alcohol-dependence and D3 dopamine receptor gene in
three independent samples. Am J Med Genet (Neuropsychiatric
Genetics) 1995; 18: 529-31.
26 Duaux E, Gorwood P, Griffon N, Bourdel MC, Sautel F, Sokoloff P,
et al. Homozygosity at the dopamine D3 receptor gene is associated
with opiate dependence. Mol Psychiatry 1998; 3: 333-6.
27 Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism.
Science 1987; 236: 410-6.
 The genetics of addiction
28 Nurnberger JI, Blehar MC, Kaufmann CA, York-Cooler C, Simp-
son SG, Harkavy-Friedman J, et al. Diagnostic Interview for Ge-
netic Studies: rational, unique features, and training. Arch Gen
Psychiatry 1994; 51: 849-62.
29 Zuckerman M, Kolin E, Price L, Zoob I. Development of sensation-
seeking scale. J Consult Clin Psychol 1964; 28: 477-82.
30 American Psychiatric Association collaboration. Diagnostic and
Statistical Manual of Mental Disorders, Revised Third Edition.
Washington, DC: American Psychiatric Association Press; 1987.
31 Galizio M, Gerstenharber L, Friedensen F. Correlates of sensation
seeking in alcoholics. Int J Addictions 1985; 20: 1479-93.
32 Kilpatrick D, Sutker P, Smith A. Deviant drug and alcohol use: the
role of anxiety, sensation seeking and other personality variables.
In: Zuckerman M, Spielberger C, editors. Emotions and Anxiety:
717
New Concepts, methods and applications. Hillsdale, NJ: Erlbaum;
1976, p. 247-78.
33 Bierut L, Dinwiddie S, Begleiter H, et al. Familial transmission
of substance dependence: alcohol, marijuana, cocaine, and habitual
smoking. A report from the collaborative study on the genetics of
alcoholism. Arch Gen Psychiatry 1998; 55: 982-8.
34 Merikangas K, Stolar M, Stevens D, et al. Familial transmission of
substance use disorders. Arch Gen Psychiatry 1998; 55: 973-9.
35 Sander T, Harms H, Podschus J, Finckh U, Nickel B, et al.
Dopamine D1, D2 and D3 receptor genes in alcohol dependence.
Psychiatr Genet 1995; 5(4): 171-6.
36 Gorwood P. Genetic association studies in behavioral neuroscience.
In: Cruzio W, Gerlai R, editors. Molecular Genetic Techniques for
Behavioral Neuroscience. Amsterdam: Elsevier; 1999, p. 113-21.