Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake
T Seif, SJ Chang, JA Simms, SL Gibb, J Dadgar… - Nature …, 2013 - nature.com
Nature neuroscience, 2013•nature.com
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 …
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 …
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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