SIR—The synonymous mutation C957T in the human D2 dopamine receptor (DRD2) has been shown to reduce mRNA stability and synthesis of the receptor in vitro¹. We studied whether this polymorphism affects in vivo DRD2 binding in 45 healthy subjects using [¹¹C]raclopride and positron emission tomography (PET). Subjects carrying the 957T allele had markedly lower striatal D2 receptor availability. This in vivo neurobiological correlate in the brain makes the C957T an interesting candidate for genetic predisposition studies in neuropsychiatric disorders.

Dopamine receptor D2 (DRD2) has been suggested to be involved in the biology of several neuropsychiatric disorders,² and is an important target for drug treatment, for example, in schizophrenia. Previous PET studies have revealed a high interindividual variation in striatal DRD2 density in vivo,^{3, 4} part of which is explained by genetic factors.⁴ Recently reported synonymous C957T polymorphism of DRD2 dramatically decreases DRD2 mRNA stability and receptor synthesis, which makes it a potent DRD2 expression-regulating factor in vitro.¹ We tested whether the DRD2 C957T polymorphism and a related modulating polymorphism, G1101A,¹ affect DRD2 density in vivo in man. DRD2 availability (binding potential, BP) was measured by using [¹¹C]raclopride and PET⁵ in a previous sample of healthy volunteers.⁴

The frequencies of C and T alleles of C957T polymorphism were comparable to frequencies in European–American population described by Duan et al.¹ 1101A allele of G1101A polymorphism did not occur in any subject in this study and thus only C957T polymorphism is included in our analysis.

A linear regression analysis indicated that the C957T genotype had a highly significant effect on DRD2 BP (P=0.004, R²=0.179) with highest BP in C/C, intermediate in C/T and lowest in T/T genotype (Figure 1). The effect of the C957T genotype on DRD2 BP was identical after adjusting for age. The C957T genotype explained 18% of the variance in the striatal DRD2 BP, whereas aging and C957T together explained 35.3% of the BP variance. We have previously reported that the A1 allele of the TaqIA RFLP associates with low striatal DRD2 BP.⁴ Therefore, we entered also the TaqIA RFLP genotype in the model that now explained 40.1% of BP variance (R²=0.401). The effect of C957T and aging remained significant in this model (P=0.028 and P=0.004, respectively), whereas the Taq1A effect on DRD2 BP variability was significant only at a trend level (P=0.080).

In accordance with the previous in vitro study,¹ we found that the C957T polymorphism associates with low DRD2 receptor binding potential in vivo. The C957T genotype explained about 18% of the striatal DRD2 BP variance, which is somewhat higher than that reported previously for the A1 allele of TaqIA RFLP (12%;⁴). The C957T and TaqIA polymorphisms have been reported to be in linkage disequilibrium.¹ The effect of TaqIA RFLP on DRD2 BP was weaker than that of C957T, but still almost statistically significant in the regression analysis. We have previously observed that the A1 allele of the TaqIA RFLP is associated with decreased inhibition of striatal dopamine synthesis in vivo ([¹⁸F]DOPA uptake), whereas the C957T polymorphism had a weaker and nonsignificant effect on this index of dopamine synthesis.⁶ In fact, the TaqIA RFLP was recently reported to be a potentially functional nonsynonymous polymorphism of a novel kinase-like gene adjacent to DRDR gene.⁷ It is possible that TaqIA RFLP has a C957T-independent effect in DRD2 BP and dopamine synthesis, although the effects of C957T polymorphism and Taq1A RFLP on these measures in our studies differ only quantitatively and not qualitatively.

The C957T polymorphism has a neurobiological correlate and endophenotype in DRD2 binding in human brain in vivo. This makes the C957T polymorphism interesting for studies on the pathophysiology and pharmacological treatment of DRD2-associated neurological and psychiatric disorders, for example, Parkinson's disease, schizophrenia and alcoholism.² DRD2 is a major target of antipsychotic drugs and further studies on the significance of C957T polymorphism in the antipsychotic drug response is warranted.