title: C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo.
abstract: 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.
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20014 Turku, Finland.
authors.forename: Mika M
authors.initials: MM
authors.lastname: Hirvonen
authors.forename: Ville
authors.initials: V
authors.lastname: Lumme
authors.forename: Jussi
authors.initials: J
authors.lastname: Hirvonen
authors.forename: Ullamari
authors.initials: U
authors.lastname: Pesonen
authors.forename: Kjell
authors.initials: K
authors.lastname: Någren
authors.forename: Tero
authors.initials: T
authors.lastname: Vahlberg
authors.forename: Harry
authors.initials: H
authors.lastname: Scheinin
authors.forename: Jarmo
authors.initials: J
authors.lastname: Hietala
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism*; D002247:Carbon Isotopes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000235:genetics; D011759:Pyrrolidines / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012457:Salicylamides / Q000378:metabolism; D055815:Young Adult
chemical_list: D002247:Carbon Isotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C065065:FLB 457