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.
aDepartment of Pharmacology and Clinical Pharmacology, University of Turku, Turku
dNeuropsychiatric Imaging, Turku PET Centre, Turku
eDepartment of Psychiatry, Turku University Central Hospital, Turku, Finland
Sponsorship: This study was financially supported by the Academy of Finland.
Correspondence and requests for reprints to Professor Jarmo Hietala, Neuropsychiatric Imaging, Turku PET Centre, Turku University Central Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
Tel: +358 2313 2891; fax: +358 2231 8191;
Received 30 April 2004 Accepted 31 January 2005