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Bioinformatics Analyses Reveal Age‐Specific Neuroimmune Modulation as a Target for Treatment of High Ethanol Drinking
Author(s) -
Agrawal Rajiv G.,
Owen Julie A.,
Levin Patricia S.,
Hewetson Aveline,
Berman Ari E.,
Franklin Scott R.,
Hogue Ryan J.,
Chen Yukun,
Walz Chris,
Colvard Benjamin D.,
Nguyen Jonathan,
Velasquez Oscar,
AlHasan Yazan,
Blednov Yuri A.,
Fowler AnnaKate,
Syapin Peter J.,
Bergeson Susan E.
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12288
Subject(s) - minocycline , in silico , druggability , medicine , pharmacology , bioinformatics , biology , gene , genetics , antibiotics
Background Use of in silico bioinformatics analyses has led to important leads in the complex nature of alcoholism at the genomic, epigenomic, and proteomic level, but has not previously been successfully translated to the development of effective pharmacotherapies. In this study, a bioinformatics approach led to the discovery of neuroimmune pathways as an age‐specific druggable target. Minocycline, a neuroimmune modulator, reduced high ethanol ( E t OH ) drinking in adult, but not adolescent, mice as predicted a priori. Methods Age and sex‐divergent effects in alcohol consumption were quantified in FVB / NJ × C 57 BL /6 J F 1 mice given access to 20% alcohol using a 4 h/d, 4‐day d rinking‐in‐ d ark ( DID ) paradigm. In silico bioinformatics pathway overrepresentation analysis for age‐specific effects of alcohol in brain was performed using gene expression data collected in control and DID ‐treated, adolescent and adult, male mice. Minocycline (50 mg/kg i.p., once daily) or saline alone was tested for an effect on E t OH intake in the F 1 and C 57 BL /6 J ( B 6) mice across both age and gender groups. Effects of minocycline on the pharmacokinetic properties of alcohol were evaluated by comparing the rates of E t OH elimination between the saline‐ and minocycline‐treated F 1 and B 6 mice. Results Age and gender differences in DID consumption were identified. Only males showed a clear developmental increase difference in drinking over time. In silico analyses revealed neuroimmune‐related pathways as significantly overrepresented in adult, but not in adolescent, male mice. As predicted, minocycline treatment reduced drinking in adult, but not adolescent, mice. The age effect was present for both genders, and in both the F 1 and B 6 mice. Minocycline had no effect on the pharmacokinetic elimination of E t OH . Conclusions Our results are a proof of concept that bioinformatics analysis of brain gene expression can lead to the generation of new hypotheses and a positive translational outcome for individualized pharmacotherapeutic treatment of high alcohol consumption.