Since 1990, association studies have amassed strong evidence implicating the D2 dopamine receptor (DRD2) gene in alcoholism. Specifically, the Taql A minor (A1) allele of the DRD2 gene has been associated with alcoholism. The DRD2 gene has also been found to be involved in other substance use disorders including cocaine, nicotine and opioid dependence, and obesity. Beyond association studies, pharmacologic studies have shown reduced brain D2 dopamine receptor numbers in A1+ allele carriers (A1A1 and A1A2 genotypes) compared to A1– allele carriers (A2A2 genotype). Through a number of other approaches, different phenotypes have also been identified in subjects with the A1+ and A1– alleles. These include metabolic, neurophysiological, neuropsychological, personality, stress and treatment studies. It is hypothesized that in an effort to compensate for deficiencies in the dopaminergic system, substance abusers may seek to stimulate the mesocorticolimbic circuits of the brain, long thought to be important in behavioral reward and reinforcement. In effect, one form of the DRD2 gene, the A1 allele, renders the dopaminergic system inefficient and rewards substance abuse that increases brain dopamine levels.

We analysed the impact of the TaqI A1 allele of the D2 dopamine receptor gene on the risk for alcoholism, trying to depict three explanations frequently proposed to explain discrepancies in association and linkage studies: that the A1 allele may act as a marker rather than as a vulnerability factor, that stratification biases and unevaluated controls may explain positive results, and that the A1 allele is modifying the phenotype rather than increasing the risk for alcoholism. We thus tested another (dinucleotide STRP) marker within the DRD2 gene, selected a new homogenous sample of 113 alcoholic patients and 49 unaffected controls strictly matched for ethnic origins, and systematically assessed both samples with a semi-structured interview to detect (in both samples) alcohol dependence, but also such related traits as specificities of complications.

The frequency of the A1 allele was not significantly different between alcoholics and controls but when comparing different subgroups of alcoholics, the A1 allele was significantly more frequent in alcoholic patients with somatic complications (OR = 3.00, CI[1.37-6.62]), social and professional complications (OR = 2.72, CI[1.25-5.90]), or with co-morbid dependence (OR = 2.88, 95% IC [1.16-7.15]). The association for co-morbid dependence and somatic complications was also positive when taking into consideration both STRP and TaqIA polymorphisms.

The A1 allele does not increase the risk for alcoholism per se in our sample, but may be involved in a related trait which is partially dependent on the diagnosis of alcoholism, through a disequilibrium with another close mutation.

Alleles of the D2 dopamine receptor (DRD2) and the alcohol dehydrogenase 2 (ADH2) genes were determined in 69 French Polynesian alcoholic patients and 57 controls matched for racial origin. Three racial groups were studied: pure Polynesians (PP), Polynesians mixed with Caucasian (PCA) ancestry and Polynesians mixed with Chinese (PCH) ancestry. DRD2 A1 allele frequencies in the alcoholics compared to their controls in these groups were: PP,.26 vs .32 (P = .69); PCA, .44 vs .35 (P = .46); PCH, .40 vs 0.39 (P = .88). ADH2 1 allele frequencies in alcoholics compared to their controls groups were: PP, .56 vs .62 (P = .66); PCA, .75 vs .56 (P = .09); PCH, .78 vs .32 (P = .009). In the PCA group, the combination of the DRD2 A1 genotypes and the ADH2 1 homozygotes was strongly associated with alcoholism (P = .0027). This preliminary study shows the importance of ascertaining racial ancestry in molecular genetic association studies. Moreover, it suggests that a combination of genes are involved in susceptibility to the development of alcoholism.

The high co-morbidity between bipolar disorder and alcohol dependence may have different explanations, one of them being the existence of common genetic factors for the two disorders. Several candidate genes may be involved but the genes acting in the dopaminergic pathway may be more specifically involved. We have thus tested the role of the gene encoding the D2 dopamine receptor (TaqI A1 allele) in the potentially shared vulnerability to alcohol dependence and bipolar disorder.

One hundred and twenty-two French (for at least two generations) patients were recruited on the basis of hospital or outpatient files and were interviewed with the DIGS. The A1 allele frequencies were compared between four groups, namely, with bipolar patients and co-morbid alcohol dependence (N = 21), with bipolar patients without alcohol morbidity (N = 31), with alcohol dependence without mood disorder (N = 35) and unaffected controls (N = 35).

The Hardy Weinberg equilibrium for the DRD2 Taq1 A1 genotypes was respected for the sample as a whole, and for each subsample. We observed that 42.9% of control subjects have at least one A1 allele, a frequency which is not significantly different from the one observed in the affected sample as a whole (39.1%), neither from patients with alcohol dependence (37.1%), patients with bipolar disorder (48.4%) nor patients with alcohol dependence and bipolar disorder (28.6%). The regression analysis based on the three variables (bipolar disorder, alcohol dependence and interaction between these two disorders) does not explain the presence of the A1 allele of the DRD2 gene.

We thus found no evidence for a significant role of the A1 allele of the D2 dopamine receptor gene in the specific association between bipolar disorder and alcohol dependence in our sample.

Addiction to various substances, including drugs and alcohol, probably arises from a combination of environmental and genetic factors. The genetic vulnerability to drug addiction is supported by several familial, adoption and twin studies. However, as in other mental disorders, the genetic vulnerability to drug addiction appears complex: these disorders do not follow the rules of Mendelian inheritance. Instead, they are probably influenced by multiple susceptibility genes, each of which contributes to the disorder. The more genes necessary for a disorder, the harder it is to detect any of them. This difficulty is magnified by the role of environmental factors. Association studies using the candidate gene approach can identify susceptibility genes for drug abuse supported by the pathophysiological hypothesis of the illness. This review will focus on the clinical and molecular genetic studies in drug abuse.

Epidemiologic studies in the general population and those based on the clinical assessment of schizophrenic populations have revealed a high degree of overlap between schizophrenia and addictive disorders. The abuse of psychoactive substances (including alcohol) throughout life is so frequent (50%) that the possibility of a specific link inevitably arises. Various hypotheses have been suggested to explain the high co-morbidity between schizophrenia and addiction: 1) The social-environmental hypothesis has been developed but studies have provided poor evidence to validate it. 2) The possible shared biological vulnerability between schizophrenia and addictions led researchers to explore common genetic determinants and study the involvement of the dopaminergic and opioid systems in the aetiology of both schizophrenia and the abuse of and dependence on psychoactive drugs. 3) Finally, the theory of self-medication suggests that schizophrenics may be attempting to counter the deficit linked to their disorders by using the substances they take or their dependency-type behaviour to cope with their emotional problems. The clinical profile of schizophrenic addicts does seem to display some distinctive features, such as the high level of depressive co-morbidity, very high nicotine and alcohol dependence, with a very poor prognosis. These patients are difficult to manage; the possibility of pharmacologic interactions between the substances they are taking and neuroleptic medication calls for prudence, and their compliance is also poor. Addictive disorders in schizophrenics are currently a topic of active research intended to lead to identifying specific treatments. The early identification of addictive disorders in schizophrenics should make it possible to limit their development and improve the prognosis.

Genetic factors explain a non-negligible part of the vulnerability to alcohol dependence, the genetic influence in males being estimated at around 60%. The search for gene(s) potentially implicated in alcoholism is counteracted by the clinical heterogeneity of alcoholism, but also by heterogeneity of the etiologic factors involved. It is thus necessary to redefine more specific phenotypes with more simple determinism, and to focus on more specific subsets of candidate genes. In this view, the existence of co-occurrence (presence at the same time, whatever the cause) between antisocial personality and alcoholism is frequently reported. Three hypotheses have been previously proposed to explain this co-occurrence. Firstly, it could be a pure artefact or contamination, due to common items in diagnostic manuals widely used, such as the DSM or ICD. Secondly, antisocial personality and alcoholism could share common etiologic factor(s), and determine a ‘real’ co-morbidity. Finally, common genetic factors between these two disorders may exist, with the observation of a co-transmission of both disorders more often than expected by chance alone, meaning the existence of co-aggregation. Each of these three hypotheses will be reviewed and discussed.

The extension of the definition of dependence leads to the consideration of some impulsive disorders as a form of dependence disorder. This pathological condition is characterized by the repetitive occurrence of impulsive and uncontrolled behaviors. Other clinical characteristics are failure to resist an impulse, drive or temptation to perform some act harmful to oneself and/or others, an increasing sense of tension or excitement before acting out, and a sense of pleasure, gratification or release at the time of the behavior or shortly thereafter. Behavioral dependences most often described are pathological gambling, kleptomania, trichotillomania and compulsive buying.

Studies using a specific assessment scale, the South Oaks Gambling Screen, distinguished problem gambling from pathological gambling. Social gamblers spend 5% of their money and pathological gamblers 14 to 45%. Prevalence of ‘problem gambling’ is 4% and pathological gambling 2%. Several studies have suggested that the incidence of pathological gambling is eight to ten times greater in alcohol-dependent patients than in the general population.

No systematic study has assessed the prevalence of kleptomania. Data come from case reports. Among subjects arrested after a theft, prevalence of kleptomania varied between 0 and 24%. Trichotillomania prevalence rate is 0.6% among students. Studies using less restrictive diagnostic criteria found a prevalence rate of 3.4% in women and 1.5% in men. The disorder is often unrecognized; 40% of the cases are not diagnosed and 58% of the patients have never been treated.

Prevalence studies of compulsive buying found a rate between 1 and 6% in the general population. Compulsive buying is significantly more frequent among women (90% of the cases). Study of family history of compulsive buyers showed a high frequency of alcohol-dependence disorder (20%) and depression (18%). In all cases of behavioral dependence disorders, a high level of impulsivity and sensation-seeking could determine an increased risk.

Alcohol withdrawal is a clinically and etiologically heterogeneous syndrome caused by a complex interaction of environmental (e.g., amount of ethanol) and genetic factors. Multiple genes are considered to be involved in various components of the syndrome, each of them contributing only modestly to withdrawal vulnerability. Association studies using candidate genes of the dopamine, serotonin, gabaergic and opioidergic systems are reviewed and methodological limitations are discussed.

All drugs abused by humans increase dopamine in the shell of nucleus accumbens, which implicate the neurons of this structure in their hedonic and reinforcing properties. Among the various dopamine receptor subtypes, the D1 (D1R) and D3 (D3R) receptors co-localise in accumbal shell neurons. Synergistic D1R/D3R interactions at this level were found on gene expression and during induction and expression of behavioral sensitisation to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitisation to abused drugs is a component of their long-term effects. Converging pharmacologic, human postmortem and genetic studies suggest the involvement of the D3R in reinforcing effects of drugs; D3R agonists reduced cocaine self-administration in rats, without disrupting the maintenance of self-administration. These data suggest the use of D3R agonists as partial substitutes to treat cocaine dependence, by affecting its reward component. However, substitution therapies maintain dependence and may be inefficient on drug craving and relapse, which are the unsolved and critical problems in the treatment of drug addiction. Recently, a highly selective and partial D3R agonist was shown to reduce cocaine-associated cue-controlled behaviour in rats, without having any primary intrinsic effects. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, such D3R agents have potential therapeutic applications.