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Nat Neurosci. 2013 Aug;16(8):1094-100. doi: 10.1038/nn.3445. Epub 2013 Jun 30.

Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake.

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1
Ernest Gallo Clinic and Research Center, University of California at San Francisco, San Francisco, California, USA.

Abstract

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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PMID:
23817545
PMCID:
PMC3939030
DOI:
10.1038/nn.3445
[Indexed for MEDLINE]
Free PMC Article

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