Effects of naltrexone are influenced by childhood adversity during negative emotional processing in addiction recovery

George Savulich ,Roberta Riccelli ,Dana Smith ,Barbara J Sahakian ,Anne Lingford-Hughes ,Remy Flechais ,David Nutt ,Marta Correia ,Laurence Reed ,Bill Deakin ,John Mcgonigle ,Louise M Paterson ,Csaba Orban ,Richard M Elliott ,Anna Murphy ,Trevor W Robbins ,Roger Tait ,Luca Passamonti ,Eleanor Taylor ,John Suckling ,Karen D Ersche

doi:10.1038/tp.2017.34

Abstract

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone (n=18, alcohol) and in combination with cocaine and/or opioid dependence (n=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence (n=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

Highlights

Suppression of negative affective states such as anxiety and withdrawal symptoms is one motivational pathway to support the consumption of alcohol.[4,5]
Connectivity between the amygdala and the hippocampus is associated with maladaptive emotional processing,[11] and alterations in hippocampal network activation and connectivity have been shown to predict relapse.[12]
We suggest that behavioral interventions that promote emotion regulation strategies for stress and/or more severe psychopathology as a consequence of combined drug taking.[85]

Summary

Introduction

As negatively reinforced drinking becomes more pronounced, negative affective states increase, thereby escalating alcohol intake and raising vulnerability to relapse after treatment.[6,7]. Functional abnormalities during negative emotional processing have been found in limbic and cortical networks in substance dependence.[1] Threat-related reactivity of the amygdala, for example, is strongly associated with negatively reinforced problem drinking.[10] Connectivity between the amygdala and the hippocampus is associated with maladaptive emotional processing,[11] and alterations in hippocampal network activation and connectivity have been shown to predict relapse.[12] The prefrontal cortex has extensive connections with subcortical structures that regulate emotional processing, including the amygdala.[13] Alcohol and drug exposure impairs emotion regulation in this region, with interconnected medial and cingulate networks showing enhanced reactivity to arousing stimuli and reduced capacity to suppress negative affect.[14] The medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) act to appraise and regulate negative emotions.[15] These cortical areas over-activate in response to substance-related and naturally evocative stimuli[16] and, together with limbic regions associated with impaired emotional processing in addiction, are candidate loci for pharmacological intervention

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