Hirvonen Mika M, Lumme Ville, Hirvonen Jussi, Pesonen Ullamari, Någren Kjell, Vahlberg Tero, Scheinin Harry, Hietala Jarmo
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20014 Turku, Finland.
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Jun 15;33(4):630-6. doi: 10.1016/j.pnpbp.2009.02.021. Epub 2009 Mar 11.
The C957T (rs6277) single nucleotide polymorphism (SNP) of the human dopamine D2 receptor (DRD2) gene (DRD2) affects DRD2 mRNA stability and has been shown to predict striatal DRD2 availability (B(max)/K(D)) in vivo in man. Specifically, the C/C genotype is associated with low striatal DRD2 availability (C/C<C/T<T/T). It is not known, however, whether this pattern of genetic regulation of DRD2 expression also applies to low density DRD2 populations in extrastriatal regions. We analyzed extrastriatal DRD2 availability (indexed by binding potential, BP(ND)) measured in 38 healthy male volunteers with 3D-PET and the high-affinity DRD2 radioligand [(11)C]FLB457. The subjects were genotyped for the C957T as well as for two other widely studied DRD2 SNPs, the TaqIA (rs1800497) and the -141C Ins/Del (rs1799732). Statistical analyses showed that the C957T C/C genotype was associated with high extrastriatal DRD2 BP(ND) throughout the cortex and the thalamus (C/C>C/T>T/T). Also the TaqIA A1 allele carriers (p=0.101) tended to have higher extrastriatal DRD2 BP(ND) compared to non-carriers whereas the -141C Ins/Del genotype did not influence extrastriatal DRD2 BP(ND). Our findings indicate that the DRD2 SNPs regulate DRD2 availability in the human cortex and in the thalamus in vivo. However, the regulation pattern is different from that observed previously for striatal DRD2 availability in vivo, which may reflect distinct functional roles of dopamine and DRD2 in the cortex versus the striatum. The results provide useful information for the interpretation of genetic studies exploring the role of the DRD2 in normal physiology as well as in psychiatric and neurological diseases.
人类多巴胺D2受体（DRD2）基因的C957T（rs6277）单核苷酸多态性（SNP）影响DRD2 mRNA的稳定性，并且已被证明能够预测人体体内纹状体DRD2的可用性（B(max)/K(D)）。具体而言，C/C基因型与低纹状体DRD2可用性相关（C/C<C/T<T/T）。然而，尚不清楚这种DRD2表达的遗传调控模式是否也适用于纹状体以外区域的低密度DRD2群体。我们分析了38名健康男性志愿者通过三维正电子发射断层扫描（3D-PET）和高亲和力DRD2放射性配体[(11)C]FLB457测量的纹状体以外区域DRD2的可用性（以结合潜能BP(ND)为指标）。对受试者进行了C957T以及另外两个广泛研究的DRD2 SNP（TaqIA，rs1800497和-141C Ins/Del，rs1799732）的基因分型。统计分析表明，C957T的C/C基因型与整个皮质和丘脑的高纹状体以外区域DRD2 BP(ND)相关（C/C>C/T>T/T）。此外，与非携带者相比，TaqIA A1等位基因携带者（p = 0.101）的纹状体以外区域DRD2 BP(ND)也往往更高，而-141C Ins/Del基因型不影响纹状体以外区域DRD2 BP(ND)。我们的研究结果表明，DRD2 SNP在人体体内调节皮质和丘脑中DRD2的可用性。然而，调控模式与先前观察到的体内纹状体DRD2可用性的调控模式不同，这可能反映了多巴胺和DRD2在皮质与纹状体中的不同功能作用。这些结果为解释探索DRD2在正常生理以及精神和神经疾病中的作用的基因研究提供了有用信息。
