C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity

Abstract

The C957T polymorphism of the human dopamine D2 receptor gene (DRD2) regulates DRD2 availability in striatum in vivo. Specifically, the T allele predicts high DRD2 availability in healthy volunteers (T/T>T/C>C/C). However, this finding was unexpected as in vitro the T allele is associated with a decrease in DRD2 mRNA stability and synthesis of the receptor through a putative alteration in the receptor mRNA folding. To elucidate further how changes in DRD2 density (B(max)) and affinity (K(D)) contribute to the differences in DRD2 availability between the C957T genotypes, we studied these parameters separately in a sample of 45 healthy volunteers. The subjects had two PET scans with [(11)C]raclopride (high and low specific radioactivity scans) for the estimation of B(max) and K(D), and were genotyped for the C957T. Moreover, the role of the related and previously studied functional TaqIA polymorphism of ankyrin repeat and kinase domain containing 1 (ANKK1) gene was reassessed for comparative purposes. The results indicate that the C957T increased binding potential by decreasing DRD2 K(D) (C/C>C/T>T/T), while B(max) was not significantly altered. These preliminary findings indicate that the C957T genotype-dependent changes in DRD2 availability are driven by alterations in receptor affinity and putatively in striatal dopamine levels. This mechanism seems to differ from that observed previously for the ANKK1 gene TaqIA polymorphism, where the minor allele (A1) affects DRD2 availability predominantly by changing B(max). The hypothesis that the two SNPs may have independent effects on dopamine neurotransmission needs to be further tested.

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“…Specifically, the T allele of the C957T SNP has been linked to reduced mRNA stability, affecting the density of D2 receptors (Duan et al, 2003). This allele has also been associated with reduced extrastriatal D2 receptor availability (Hirvonen et al, 2009a) and lower striatal DA levels (Hirvonen et al, 2009b).…”

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“…2003), and also with higher D2 dopamine receptors availability due to low density (Bmax activity) and high affinity (low K d values) in the human striatum (Hirvonen et al. 2009a). In this scenario, the hypothesis of a net reduction of the D2 receptor function by reducing the dopamine tone in the striatum is feasible.…”

“…In any case, several imaging studies have demonstrated the C957T effect upon D2 receptors in the brain (Hirvonen et al. 2004, 2009a,b). Moreover, C957T SNP is also a marker of a genomic sequence at the 5′ UTR of ANKK1 gene.…”

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“…In the context of drugs of abuse that increase dopamine release, individuals with the val/val genotype show improved prefrontal efficiency (reduced activity at the same level of performance) during working memory performance following amphetamine administration (Mattay et al, 2003), whereas smokers with val/val genotypes show improved performance and increased prefrontal activity following nicotine exposure vs abstinence (Loughead et al, 2009). The T allele of the dopamine D2 receptor (DRD2) C957T variant, considered a reduced activity variant (Hirvonen et al, 2009), is also associated with reduced working memory and processing efficiency following nicotine administration (Jacobsen et al, 2006). Although it is difficult to draw conclusions from a single study of psychiatric treatment, emerging data on the effects of drugs of abuse suggest that individuals who carry putative reduced activity alleles for genes related to dopamine signaling may be more responsive to the cognitive enhancing effects of stimulating drugs.…”

“…Met allele codes for lower activity protein because of thermal instability; associated with higher intracellular DA levels due to decreased degradation, and typically associated with better performance on executive function tasks (Egan et al, 2001). b T allele associated with reduced mRNA stability, lower expression of DRD2 receptors, and reduced receptor affinity (Hirvonen et al, 2009). c Synonymous SNP; functional consequences uncertain (Domschke et al, 2008).…”