Association of norepinephrine transporter methylation with in vivo NET expression and hyperactivity–impulsivity symptoms in ADHD measured with PET

Sigurdardottir, Helen; Kranz, Georg S.; Rami‐Mark, Christina; James, G.M.; Vanicek, Thomas; Gryglewski, Gregor; Berroterán-Infante, Neydher; Kautzky, Alexander; Hienert, Marius; Traub-Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hartmann, Andréas; Hacker, Marcus; Rujescu, Dan; Kasper, Siegfried; Lanzenberger, Rupert

doi:10.1038/s41380-019-0461-x

Cited by 27 publications

(15 citation statements)

References 49 publications

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“…Attention deficit/hyperactivity disorder (ADHD) is the archetypal neurocognitive condition characterized by attentional control deficits. There is evidence that norepinephrine (NE) transmission is altered in ADHD (6)(7)(8), which is consistent with the use of NE-boosting drugs as pharmacological therapies for this disorder (9)(10)(11).…”

mentioning

confidence: 64%

Differential attentional control mechanisms by two distinct noradrenergic coeruleo-frontal cortical pathways

Bari

Pignatelli

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The attentional control of behavior is a higher-order cognitive function that operates through attention and response inhibition. The locus coeruleus (LC), the main source of norepinephrine in the brain, is considered to be involved in attentional control by modulating the neuronal activity of the prefrontal cortex (PFC). However, evidence for the causal role of LC activity in attentional control remains elusive. Here, by using behavioral and optogenetic techniques, we investigate the effect of LC neuron activation or inhibition in operant tests measuring attention and response inhibition (i.e., a measure of impulsive behavior). We show that LC neuron stimulation increases goal-directed attention and decreases impulsivity, while its suppression exacerbates distractibility and increases impulsive responding. Remarkably, we found that attention and response inhibition are under the control of two divergent projections emanating from the LC: one to the dorso-medial PFC and the other to the ventro-lateral orbitofrontal cortex, respectively. These findings are especially relevant for those pathological conditions characterized by attention deficits and elevated impulsivity.

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mentioning

confidence: 64%

Differential attentional control mechanisms by two distinct noradrenergic coeruleo-frontal cortical pathways

Bari

Pignatelli

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…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).…”

Section: F-fmener-dmentioning

confidence: 85%

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

et al. 2020

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The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used 123/131 I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. 11 C-HED and 18 F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed.

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“…This last aspect may be critical in moving forward to examine MPH-induced FC changes in clinical populations (i.e. ADHD), who may have alterations in the distribution of DAT [88] and NET [90].…”

Section: Discussionmentioning

confidence: 99%

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

Dipasquale

Martins

Sethi

et al. 2020

Neuropsychopharmacol.

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Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Our main analysis showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. In our exploratory analysis, we found that MPH-induced regional variations in the DAT and NET-enriched FC maps were significantly correlated with some of the inter-individual differences on key behavioural responses associated with the reinforcement-learning task. Our findings show that main MPH-related FC changes at rest can be understood through the distribution of DAT in the brain. Furthermore, they suggest that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to engagement of distinct molecular targets.

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Association of norepinephrine transporter methylation with in vivo NET expression and hyperactivity–impulsivity symptoms in ADHD measured with PET

Cited by 27 publications

References 49 publications

Differential attentional control mechanisms by two distinct noradrenergic coeruleo-frontal cortical pathways

Differential attentional control mechanisms by two distinct noradrenergic coeruleo-frontal cortical pathways

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

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

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