Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

• Published in: Synapse (New York, N.Y.) N.Y.), 2016-10, Vol.70 (10), p.418-431
• Main Authors: Eisenstein, Sarah A., Bogdan, Ryan, Love-Gregory, Latisha, Corral-Frías, Nadia S., Koller, Jonathan M., Black, Kevin J., Moerlein, Stephen M., Perlmutter, Joel S., Barch, Deanna M., Hershey, Tamara
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Alleles; Ankyrin Repeat - genetics; Benperidol - analogs & derivatives; Benperidol - pharmacokinetics; Case-Control Studies; Corpus Striatum - diagnostic imaging; Corpus Striatum - metabolism; dopamine; Female; Heterozygote; Humans; Male; Middle Aged; Obesity - genetics; PET; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals - pharmacokinetics; Receptors, Dopamine D2 - chemistry; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; rs1800497; Schizophrenia; Schizophrenia - genetics
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.21916

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[11C]methyl)benperidol ([11C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1−), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10–14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1− was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R‐selective [11C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. We investigated the difference in striatal dopamine D2 receptor binding, as measured by PET with (N‐[11C]methyl)benperidol ([11C]NMB), between A1 allele carriers (A1+) and individuals homozygous for the A2 allele (A1‐) of the DRD2/ANKK1 TaqIA single nucleotide polymorphism. In Study 1, A1+ had 5–12% less striatal [11C]NMB binding than A1‐.