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Alcohol Clin Exp Res. 2019 Mar 8. doi: 10.1111/acer.13999. [Epub ahead of print]

Naltrexone acutely enhances connectivity between the ventromedial prefrontal cortex and a left frontoparietal network.

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Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, 27599, USA.
Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC, 27599, USA.
Department of Psychiatry, University of North Carolina, Chapel Hill, NC, 27599, USA.
Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, 27599, USA.



Naltrexone, an opioid receptor antagonist that is FDA-approved for treating alcohol use disorder (AUD), reduces alcohol craving and intake. Despite known pharmacological properties, little is known regarding the effects of naltrexone on neural circuit function. Thus, a data-driven examination of the neural effects of naltrexone in human subjects may offer novel insight into its treatment mechanisms.


Twenty-one alcohol using males (22-39) participated in a double-blind, placebo-controlled crossover study of the effects of naltrexone on brain voxel-wise functional connectivity (FC) using inter-subject FC correlation (ISFCC) mapping. We first cross-correlated the time series from each gray matter voxel to produce a 6356×6356 FC matrix for each subject and session. We then subtracted the placebo FC matrix from the naltrexone FC matrix. To identify brain regions demonstrating significant reconfiguration of whole-brain FC patterns following naltrexone treatment, we statistically quantified the consistency of patterns of voxel FC changes across subjects. Permutation testing identified significant clusters of voxels undergoing significant reconfiguration. Using the identified clusters in a seed-based functional connectivity analysis, we then compared the FC patterns of affected brain areas on placebo versus naltrexone in a paired t-test. Ridge regression analyses identified self-report measures, including substance use, that significantly predicted individual differences in FC among naltrexone-modulated regions.


Two clusters in the rostral anterior cingulate cortex (rACC)/ventromedial prefrontal cortex (vmPFC) demonstrated significant modulation of FC by naltrexone. Using these two proximal clusters as a single seed, specific FC changes were identified in regions associated with a left frontoparietal network (increasing), as well as visual and motor regions (decreasing). Stronger FC between the rACC/vmPFC and this set of regions on placebo was associated with more external locus of control, whereas weaker connectivity was associated with greater substance use problems. Naltrexone strengthened these connections most among individuals who reported greater drinking to cope.


Enhancing connectivity between the rACC/vmPFC, implicated in alcohol craving, and components of a left frontoparietal network involved in executive control may represent an effective strategy for the treatment of AUD. This article is protected by copyright. All rights reserved.


fMRI ; medial prefrontal cortex; naltrexone; resting state


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