Resting‐state functional connectivity and presynaptic monoamine signaling in Alcohol Dependence

Abstract

Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting state fMRI functional connectivity analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting state FC in 4 networks in alcoholics compared to controls (p<0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (p<0.05, corrected), but not controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles.

Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder

“…2b,c and Supplementary Table S2 ). In addition, we performed an EWAS on neuroimaging network activation as a function of alcohol use with peripheral blood from individuals with AUD that previously underwent resting state functional connectivity (RSFC) analysis 36 ( n = 68) ( Supplementary Table S3 ). Results of these 3 EWAS did yield various methylation sites that were associated with disease phenotypes ( Fig.…”

A Functional Vesicular Monoamine Transporter 1 (VMAT1) Gene Variant Is Associated with Affect and the Prevalence of Anxiety, Affective, and Alcohol Use Disorders in a Longitudinal Population-Representative Birth Cohort Study

“…It has been found that the gain-of-function A-allele (136Ile) is protective against bipolar disorder ( Lohoff et al, 2006 ), and the AA (Ile/Ile) homozygotes have lower STAI state and trait scores ( Lohoff et al, 2008b ). Very recently, the A-allele (136Ile) has been found to be associated with reduced connectivity in networks that show a general increased connectivity in alcoholics, indicating a potential protective effect ( Zhu et al, 2015 ).…”

Aberrations of anterior insular cortex functional connectivity in nontreatment-seeking alcoholics

“…These taskfree fMRI data can be used to extract resting state networks (RSNs), which consist of brain regions that are temporally -and presumably functionally --coupled (Greicius, 2008;Greicius et al, 2003;Lowe et al, 2000). There is now an emergent literature on alterations in FC within the AUD population, although most of the work has been done in abstinent individuals (Camchong et al, 2013;Chanraud et al, 2011;Jansen et al, 2015;Müller-Oehring et al, 2015;Sjoerds et al, 2017;Zhu et al, 2015). There are only a few studies that report findings in either at-risk drinkers (Vergara et al, 2017) or currently drinking alcoholdependent subjects (Weiland et al, 2014;Zhu et al, 2015), albeit with equivocal results.…”