title: 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 (FC) 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 in 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.
authors.affiliation: Section on Brain and Electrophysiology and Imaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Nisha
authors.initials: N
authors.lastname: Dutta
authors.affiliation: Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Helton
authors.affiliation: Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Schwandt
authors.affiliation: Section on Human Psychopharmacology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jia
authors.initials: J
authors.lastname: Yan
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.affiliation: Section on Brain and Electrophysiology and Imaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Cortes
authors.affiliation: Section on Brain and Electrophysiology and Imaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mike
authors.initials: M
authors.lastname: Kerich
authors.affiliation: Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Hall
authors.affiliation: Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.affiliation: Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Monte
authors.initials: M
authors.lastname: Phillips
authors.affiliation: Section on Brain and Electrophysiology and Imaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Reza
authors.initials: R
authors.lastname: Momenan
authors.affiliation: Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Falk W
authors.initials: FW
authors.lastname: Lohoff
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000098:blood supply* / Q000473:pathology*; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000098:blood supply / Q000473:pathology; D010100:Oxygen / Q000097:blood; D025341:Principal Component Analysis; D011569:Psychiatric Status Rating Scales; D012146:Rest; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics
chemical_list: C493449:SLC18A1 protein, human; D050493:Vesicular Monoamine Transport Proteins; D010100:Oxygen
keywords: SLC18A1; genetics; mPFC; monoamine transporter; presynaptic; resting-state