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dc.contributor.authorBalan, I.
dc.contributor.authorWarnock, K.T.
dc.contributor.authorPuche, A.
dc.date.accessioned2019-05-17T13:21:14Z
dc.date.available2019-05-17T13:21:14Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85047569709&doi=10.3390%2fbrainsci8040072&partnerID=40&md5=c83988fd238f0417424c7d36149ea40f
dc.identifier.urihttp://hdl.handle.net/10713/9164
dc.description.abstractAlcoholism 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.en_US
dc.description.urihttps://dx.doi.org/10.3390/brainsci8040072en_US
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofBrain Sciences
dc.subjectAlcohol/nicotine abuseen_US
dc.subjectCRF/THen_US
dc.subjectGABA A alpha2en_US
dc.subjectHSV siRNA vectorsen_US
dc.subjectPKA/CREBen_US
dc.subjectTLR4 signalen_US
dc.titleThe GABA a receptor α2 subunit activates a neuronal TLR4 signal in the ventral tegmental area that regulates alcohol and nicotine abuseen_US
dc.title.alternativeGABA A Receptor alpha2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuseen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/brainsci8040072


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