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Prefrontal Cortex Activation and Stopping Performance Underlie the Beneficial Effects of Atomoxetine on Response Inhibition in Healthy Volunteers and Those With Cocaine Use Disorder.

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Zhukovsky, Peter 
Morein-Zamir, Sharon 
Fernandez-Egea, Emilio 
Meng, Chun 


BACKGROUND: Impaired response inhibition in individuals with cocaine use disorder (CUD) is hypothesized to depend on deficient noradrenergic signaling in corticostriatal networks. Remediation of noradrenergic neurotransmission with selective norepinephrine reuptake inhibitors such as atomoxetine may therefore have clinical utility to improve response inhibitory control in CUD. METHODS: We carried out a randomized, double-blind, placebo-controlled, crossover study with 26 participants with CUD and 28 control volunteers investigating the neural substrates of stop-signal inhibitory control. The effects of a single dose of atomoxetine (40 mg) were compared with placebo on stop-signal reaction time performance and functional network connectivity using dynamic causal modeling. RESULTS: We found that atomoxetine speeded Go response times in both control participants and those with CUD. Improvements in stopping efficiency on atomoxetine were conditional on baseline (placebo) stopping performance and were directly associated with increased inferior frontal gyrus activation. Further, stopping performance, task-based brain activation, and effective connectivity were similar in the 2 groups. Dynamic causal modeling of effective connectivity of multiple prefrontal and basal ganglia regions replicated and extended previous models of network function underlying inhibitory control to CUD and control volunteers and showed subtle effects of atomoxetine on prefrontal-basal ganglia interactions. CONCLUSIONS: These findings demonstrate that atomoxetine improves response inhibition in a baseline-dependent manner in control participants and in those with CUD. Our results emphasize inferior frontal cortex function as a future treatment target owing to its key role in improving response inhibition in CUD.



Cocaine addiction, Connectivity, DCM, Impulsivity, Norepinephrine, Stop-signal task, fMRI, Humans, Atomoxetine Hydrochloride, Adrenergic Uptake Inhibitors, Healthy Volunteers, Cross-Over Studies, Inhibition, Psychological, Prefrontal Cortex, Cocaine

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Biol Psychiatry Cogn Neurosci Neuroimaging

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Elsevier BV
Medical Research Council (MR/J012084/1)
Medical Research Council (MC_G0802534)
Wellcome Trust (105602/Z/14/Z)
This work was funded by a grant of the Medical Research Council (MR/J012084/1 to TWR, KDE, BJS, ETB) and financially supported by the NIHR Cambridge Biomedical Research Centre and conducted within the Behavioural and Clinical Neuroscience Institute (BCNI). It is also part of PZ’s PhD thesis, which is available online BJS consults for Cambridge Cognition, Greenfield BioVentures and Cassava Sciences. BJS received funding from the Wallitt Foundation and Eton College and her research is conducted within the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health and Neurodegeneration Themes and the NIHR MedTech and in vitro diagnostic Co-operative (MIC), Cambridge. TWR consults for Cambridge Cognition, and recently for Greenfield Bioventures, Cassava Sciences, Arcadia, Merck, Sharpe and Dohme, and Lundbeck. He currently receives research grants from Shionogi and GlaxoSmithKline. CM was supported by a Wellcome Trust grant to KDE (105602/Z/14/Z) and the NIHR Cambridge Biomedical Research Centre. PZ was supported by the Pinsent Darwin studentship from the Department of Physiology, Development and Neuroscience, University of Cambridge. The remaining authors declare no conflict of interests. KDE was supported by an Alexander von Humboldt Fellowship for senior researchers (GBR 1202805 HFST-E) and JWD currently receives research grants from Boehringer Ingelheim and GlaxoSmithKline.