Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake.
Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake.
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DOI：
10.1038/nn.3445
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发表时间：
2013-08
影响因子：
25
通讯作者：
Hopf, F. Woodward
中科院分区：
文献类型：
--
作者：
Seif, Taban;Chang, Shao-Ju;Simms, Jeffrey A.;Gibb, Stuart L.;Dadgar, Jahan;Chen, Billy T.;Harvey, Brandon K.;Ron, Dorit;Messing, Robert O.;Bonci, Antonello;Hopf, F. Woodward
Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats. Aversion-resistant intake was associated with a new type of NMDA receptor adaptation, in which hyperpolarization-active NMDA receptors were present at mPFC and insula but not amygdalar inputs in the NAcore. Accordingly, inhibition of Grin2c NMDA receptor subunits in the NAcore reduced aversion-resistant alcohol intake. None of these manipulations altered intake when alcohol was not paired with an aversive consequence. Our results identify a mechanism by which hyperpolarization-active NMDA receptors under mPFC- and insula-to-NAcore inputs sustain aversion-resistant alcohol intake.
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