The genetics of addiction: alcohol-dependence and D3 dopamine receptor gene.

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 Ball DRD3 locus was more frequently observed in opiate dependent patients with high sensation seeking scores. In this study, we analyzed the distribution of Ball 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.

Genetic vulnerability to drug abuse.

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.

Homozygosity at the dopamine D3 receptor gene is associated with opiate dependence.

Anatomical, pharmacological and human post-mortem studies suggest the dopamine D3 receptor (DRD3) gene as a candidate for drug dependence. We thus performed an association study of the Bal I polymorphism at the DRD3 gene, including 54 opiate addicts and 70 controls. Opiate addicts had a higher sensation-seeking score (on the Zückerman scale) than controls (P = 0.001), particularly a subgroup (70%) who had a distinctly higher score, exceeding 24. There were no marked differences in genotypes between patients as a whole and controls. However, patients with a sensation-seeking score above 24 were more frequently homozygotes for both alleles than patients with a sensation-seeking score under 24 (P = 0.038) or controls (P = 0.034). Although obtained in a sample of limited size, these results suggest that the DRD3 gene may have a role in drug dependence susceptibility in individuals with high sensation-seeking scores. This hypothesis is consistent with the role of DRD3 in mediating responses to drugs of abuse in animals and the association of homozygosity at the Bal I polymorphism with drug abuse in schizophrenic patients (see companion article by Krebs et al).