Journal
NATURE NEUROSCIENCE
Volume 16, Issue 8, Pages 1094-U162Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3445
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Funding
- NIAAA [RO1AA015358]
- National Institute on Drug Abuse [F32DA028065]
- NIAAA/NIH [RO1A/MH13438]
- State of California for medical research for alcohol substance abuse through the University of California San Francisco
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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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