Dataset Information

Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals.

ABSTRACT: Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.

SUBMITTER: Morris LS

PROVIDER: S-EPMC5811832 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals.

Morris Laurel S LS Baek Kwangyeol K Tait Roger R Elliott Rebecca R Ersche Karen D KD Flechais Remy R McGonigle John J Murphy Anna A Nestor Liam J LJ Orban Csaba C Passetti Filippo F Paterson Louise M LM Rabiner Ilan I Reed Laurence L Smith Dana D Suckling John J Taylor Eleanor M EM Bullmore Edward T ET Lingford-Hughes Anne R AR Deakin Bill B Nutt David J DJ Sahakian Barbara J BJ Robbins Trevor W TW Voon Valerie V

Addiction biology 20170228 1

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-ba ...[more]

PMID: 28247526

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Project description:Alcohol use disorder (AUD) is a worldwide public health problem and a polygenetic disorder displaying substantial individual variation. This work aimed to study individual differences in behavior and its association to voluntary alcohol intake and subsequent response to naltrexone in a seamless heterogenic group of animals. Thus, by this approach the aim was to more accurately recapitulate the existing heterogeneity within the human population. Male Wistar rats from three different suppliers (Harlan Laboratories B.V., RccHan™:WI; Taconic Farms A/S, HanTac:WH; and Charles River GmbH, Crl:WI) were used to create a heterogenic group for studies of individual differences in behavior, associations to intermittent voluntary alcohol intake and subsequent response to naltrexone. The rats were tested in the open field prior to the Y-maze and then given voluntary intermittent access to alcohol or water in the home cage for 6 weeks, where after, naltrexone in three different doses or saline was administered in a Latin square design over 4 weeks and alcohol intake and preference was measured. However, supplier-dependent differences and concomitant skew subgroup formations, primarily in open field behavior and intermittent alcohol intake, resulted in a shifted focus to instead study voluntary alcohol intake and preference, and the ensuing response to naltrexone in Wistar rats from three different suppliers. The results showed that outbred Wistar rats are diverse with regard to voluntary alcohol intake and preference in a supplier-dependent manner; higher in RccHan™:WI relative to HanTac:WH and Crl:WI. The results also revealed supplier-dependent differences in the effect of naltrexone that were dose- and time-dependent; evident differences in high-drinking RccHan™:WI rats relative to HanTac:WH and Crl:WI rats. Overall these findings render RccHan™:WI rats more suitable for studies of individual differences in voluntary alcohol intake and response to naltrexone and further highlight the inherent heterogeneity of the Wistar strain. The overall results put focus on the importance of thoroughly considering the animals used to aid in study design and for comparison of reported results.

Project description:BACKGROUND:Alcohol use disorder (AUD) is known to have adverse effects on brain structure and function. Multimodal assessments investigating volumetric, diffusion, and cognitive characteristics may facilitate understanding of the consequences of long-term alcohol use on brain circuitry, their structural impairment patterns, and their impact on cognitive function in AUD. METHODS:Voxel- and surface-based volumetric estimations, diffusion tensor imaging (DTI), and neuropsychological tests were performed on 60 individuals: 30 abstinent individuals with AUD (DSM-IV) and 30 healthy controls. Group differences in the volumes of cortical and subcortical regions, fractional anisotropy (FA), axial and radial diffusivities (AD and RD, respectively), and performance on neuropsychological tests were analyzed, and the relationship among significantly different measures was assessed using canonical correlation. RESULTS:AUD participants had significantly smaller volumes in left pars orbitalis, right medial orbitofrontal, right caudal middle frontal, and bilateral hippocampal regions, lower FA in 9 white matter (WM) regions, and higher FA in left thalamus, compared to controls. In AUD, lower FA in 6 of 9 WM regions was due to higher RD and due to lower AD in the left external capsule. AUD participants scored lower on problem-solving ability, visuospatial memory span, and working memory. Positive correlations of prefrontal cortical, left hippocampal volumes, and FA in 4 WM regions with visuospatial memory performance and negative correlation with lower problem-solving ability were observed. Significant positive correlation between age and FA was observed in bilateral putamen. CONCLUSIONS:Findings showed specific structural brain abnormalities to be associated with visuospatial memory and problem-solving ability-related impairments observed in AUD. Higher RD in 6 WM regions suggests demyelination, and lower AD in left external capsule suggests axonal loss in AUD. The positive correlation between FA and age in bilateral putamen may reflect accumulation of iron depositions with increasing age.

Dataset Information

Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals.

Publications

Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals.

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