Positron emission tomography (PET) studies have revealed significant interindividual variation in dopamine D 2 receptor density in vivo in human striatum. 1 Low D 2 receptor binding in vivo has been found to associate with alcohol/substance dependence. [2][3][4][5][6] It has been suggested that the A1 allele of human D 2 receptor gene might be associated to a specific type of alcoholism 7 and possibly to a reduced D 2 receptor density in vitro. 8 We have determined D 2 dopamine receptor-binding density (B max ), affinity (K d ) and availability (B max /K d ) in 54 healthy Finnish volunteers using PET and [ 11 C]raclopride in order to determine whether the A1 allele is associated with a 'baseline' difference in D 2 receptor characteristics in vivo. A statistically significant reduction in D 2 receptor availability reflecting an alteration in receptor density was observed in the A1/A2 genotype group compared to the A2/A2 group. There was no difference in apparent K d between the two groups. In conclusion, the association between the A1 allele and low D 2 receptor availability in healthy subjects indicates that the A1 allele of the TaqIA polymorphism might be in linkage disequilibrium with a mutation in the promoter/regulatory gene element that affects dopamine D 2 receptor expression. This study provides an in vivo neurobiological correlate to the A1 allele in healthy volunteers.The dopaminergic system plays a major role in the regulation of movement, hormone secretion, mood and various motivational behaviors related to reward and reinforcement. While the contribution of the dopaminergic system has frequently been implicated in the etiology of alcohol/drug dependence, the mechanisms underlying this have remained unclear. It has been suggested that genetic factors might contribute individual differences in the regulation of D 2 receptor density and liability for predisposition to alcohol/drug dependence. This is supported by recent positron emission tomography (PET) studies which have consistently demonstrated that alcohol, 2,3 cocaine 4,5 and opiate 6 abusers have lower striatal D 2 receptor availability in vivo compared to healthy volunteers. The molecular basis of the possible hereditary factors in the dopaminergic system affecting predisposition to alcohol/drug dependence have remained unknown. The three nucleotide substitutions causing alteration in amino acid sequence found in the coding region of the D 2 dopamine receptor gene have been revealed to be relatively rare 9 and without clear effect on the D 2 receptor function in vivo. 10 While some regulatory sequences and promoter regions have been identified for human D 1 , 11 D 5 12 and rat D 2 13-15 receptors within the 5′ flanking region, little is known about the molecular events that regulate the transcription of the human D 2 receptor. From the several polymorphic gene markers, the A1 allele of TaqIA RFLP within the D 2 receptor gene suggests association with a specific type of alcoholism. 7 Despite numerous case-control studies, 16 the role of the A1 al...

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A common 44-base pair insertion/deletion polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene has been observed to be associated with affective illness and anxiety-related traits. This biallelic functional polymorphism, designated long (L) and short (S), affects 5-HTT gene expression since the S promoter is less active than the L promoter. Since there is strong evidence of a disturbance in brain serotonergic transmission among antisocial, impulsive, and violent type 2 alcoholic subjects, we decided to test the hypothesis that the frequency of the S allele, which is associated with reduced 5-HTT gene expression, is higher among habitually violent type 2 alcoholics when compared with race and gender-matched healthy controls and non-violent late-onset (type 1) alcoholics. The 5-HTT promoter genotype was determined by a PCRbased method in 114 late onset (type 1) non-violent alcoholics, 51 impulsive violent recidivistic offenders with early onset alcoholism (type 2), and 54 healthy controls. All index subjects and controls were white Caucasian males of Finnish origin. The S allele frequency was higher among type 2 alcoholics compared with type 1 alcoholics ( 2 = 4.86, P = 0.028) and healthy controls ( 2 = 8.24, P = 0.004). The odds ratio for SS genotype vs LL genotype was 3.90, 95% Cl 1.37-11.11, P = 0.011 when type 2 alcoholics were compared with healthy controls. The results suggest that the 5-HTT 'S' promoter polymorphism is associated with an increased risk for early onset alcoholism associated with antisocial personality disorder and impulsive, habitually violent behavior.

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