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Pharmacogenetics and Genomics:
Original Articles

The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects

Laakso, Akia; Pohjalainen, Tiinaa; Bergman, Jörgenb; Kajander, Jaanaa d; Haaparanta, Merjac; Solin, Olofb; Syvälahti, Erkkaa; Hietala, Jarmod e

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Abstract

The A1 allele of the TaqI restriction fragment length polymorphism (RFLP) of the human dopamine D2 receptor gene (DRD2) is associated with a low density of D2 dopamine receptors in the striatum. Because of the important role of D2 autoreceptors in regulating dopamine synthesis, we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain. We also studied the effects of two other DRD2 polymorphisms, C957 T and −141C Ins/Del, which have been suggested to affect D2 receptor levels in brain. The relationships between the TaqIA RFLP, C957 T and −141C Ins/Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [18F]fluorodopa ([18F]FDOPA), a radiolabelled analog of the dopamine precursor L-DOPA. Heterozygous carriers of the A1 allele (A1/A2; 10 subjects) had significantly higher (18%) [18F]FDOPA uptake in the putamen than subjects without the A1 allele (A2/A2; 23 subjects). C957 T and −141C Ins/Del polymorphisms did not significantly affect [18F]FDOPA Ki values. These results demonstrate that the A1 allele of DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g. β-phenylethylamine) synthesis. The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function, and suggests that dopamine and/or trace amine synthesis rate is increased in the brains of A1 allele carriers.

© 2005 Lippincott Williams & Wilkins, Inc.

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