STUDIES OF THE POTENTIAL ROLE OF THE DOPAMINE D-1 RECEPTOR GENE IN ADDICTIVE BEHAVIORS

Abnormalities in the dopaminergic reward pathways have frequently been implicated in substance abuse and addictive behaviors. Recent studies by Self and coworkers have suggested an important interaction between the dopamine D-1 and D-2 receptors in cocaine abuse. To test the hypo thesis that the DRD1 gene might play a role in addictive behaviors we examined the alleles of the Dde I polymorphism in three independent gr oups of subjects with varying types of compulsive, addictive behaviors - Tourette syndrome probands, smokers and pathological gamblers. In a ll three groups there was a significant increase in the frequency of h omozygosity for the DRD1 Dde I 1 or 2 alleles in subjects with addicti ve behaviors. The DRD1 11 or 22 genotype was present in 41.3% of 63 co ntrols and 57.3% of 227 TS probands (P = 0.024). When 23 quantitative traits were examined by ANOVA those carrying the 11 genotype consisten tly had the highest scores. Based on these results, we examined the pr evalence of the 11 genotype in controls, TS probands without a specifi c behavior, and TS probands with a specific behavior. There was a prog ressive, linear increase, significant at alpha less than or equal to 0 .005 for scores for gambling, alcohol use and compulsive shopping. Pro blems with three additional behaviors, drug use, compulsive eating and smoking were significant at alpha less than or equal to 0.05. All six variables were related to addictive behaviors. In a totally separate group of controls and individuals attending a smoking cessation clinic , and smoking at least one pack per day, 39.3% of the controls versus 66.1% of the smokers carried the 11 or 22 genotype (P = 0.0002). In a third independent group of pathological gamblers, 55.3% carried the 11 or 22 genotype (P = 0.009 vs the combined controls). In the TS group and smokers there was a significant additive effect of the DRD1 and DR D2 genes. The results for both the DRD1 and DRD2 genes, which have opp osing effects on cyclic AMP, were consistent with negative and positiv e heterosis, respectively. These results support a role for genetic va riants of the DRD1 gene in some addictive behaviors, and an interactio n of genetic variants at the DRD1 and DRD2 genes.