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    The GABA a receptor α2 subunit activates a neuronal TLR4 signal in the ventral tegmental area that regulates alcohol and nicotine abuse

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    Author
    Balan, I.
    Warnock, K.T.
    Puche, A.
    Date
    2018
    Journal
    Brain Sciences
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    Other Titles
    GABA A Receptor alpha2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse
    See at
    https://dx.doi.org/10.3390/brainsci8040072
    Abstract
    Alcoholism initiates with episodes of excessive alcohol drinking, known as binge drinking, which is one form of excessive drinking (NIAAA Newsletter, 2004) that is related to impulsivity and anxiety (Ducci et al., 2007; Edenberg et al., 2004) and is also predictive of smoking status. The predisposition of non-alcohol exposed subjects to initiate binge drinking is controlled by neuroimmune signaling that includes an innately activated neuronal Toll-like receptor 4 (TLR4) signal. This signal also regulates cognitive impulsivity, a heritable trait that defines drug abuse initiation. However, the mechanism of signal activation, its function in dopaminergic (TH+) neurons within the reward circuitry implicated in drug-seeking behavior [viz. the ventral tegmental area (VTA)], and its contribution to nicotine co-abuse are still poorly understood. We report that the γ-aminobutyric acidA receptor (GABAAR) α2 subunit activates the TLR4 signal in neurons, culminating in the activation (phosphorylation/nuclear translocation) of cyclic AMP response element binding (CREB) but not NF-kB transcription factors and the upregulation of corticotropin-releasing factor (CRF) and tyrosine hydroxylase (TH). The signal is activated through α2/TLR4 interaction, as evidenced by co-immunoprecipitation, and it is present in the VTA from drug-untreated alcohol-preferring P rats. VTA infusion of neurotropic herpes simplex virus (HSV) vectors for α2 (pHSVsiLA2) or TLR4 (pHSVsiTLR4) but not scrambled (pHSVsiNC) siRNA inhibits signal activation and both binge alcohol drinking and nicotine sensitization, suggesting that the α2-activated TLR4 signal contributes to the regulation of both alcohol and nicotine abuse. Copyright 2018 by the authors. Licensee MDPI, Basel, Switzerland.
    Keyword
    Alcohol/nicotine abuse
    CRF/TH
    GABA A alpha2
    HSV siRNA vectors
    PKA/CREB
    TLR4 signal
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85047569709&doi=10.3390%2fbrainsci8040072&partnerID=40&md5=c83988fd238f0417424c7d36149ea40f; http://hdl.handle.net/10713/9164
    ae974a485f413a2113503eed53cd6c53
    10.3390/brainsci8040072
    Scopus Count
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    UMB Open Access Articles 2018

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