Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET

Abstract

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)‐[18F]FMeNER‐D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI‐TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype‐dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (−3081 A/T) and a 5′‐untranslated region (5′UTR) SNP (−182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3′UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884–895, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype – a placebo controlled fMRI study

“…Contrary to these findings, another recent study indicated highe r NET availability in the thalamus ( Sigurdardottir et al, 2016 ) in healthy [T] carriers, supporting potential alternative explanations. More research considering the distinct underlying network dynamics is necessary to reveal the complex interactions between NET genetics, NET availability and function, and connectivity differences.…”

Factors Influencing the Cardiovascular Response to Subanesthetic Ketamine: A Randomized, Placebo-Controlled Trial

“…But in line with our hypothesis, we interpreted the observed rapid blood pressure response as being a consequence of higher NE levels at the peripheral effector cells caused by the reduced expression of NET in [T] carriers ( Kim, 2006 ) and consequently impaired reuptake capacity. Another explanation could be that differences in the central NET expression lead to reduced central counter mechanisms for the blood pressure rise in [T] carriers ( Okamoto et al, 2012 ; Sigurdardottir et al, 2016 ). The information about this genetic difference contributes to future individual tailoring of patient medication.…”

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

“…In contrast to the application of 11 C-MRB in ADHD, a study on 18 F-FMeNER-D 2 PET by Vanicek et al (2014) found no significant difference in either NET availability or distribution in ADHD-relevant regions of the brain. However, Sigurdardottir et al (2016) used it to identify the genotype-dependent difference in NET BP ND between healthy controls and ADHD patients. It provided further evidence of NET imbalance in several brain areas, pointing to epigenetic dysfunction in ADHD (Sigurdardottir et al 2019).…”