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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Deterrents / pharmacology*
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Alcohol Drinking / blood
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Alcohol Drinking / drug therapy
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Alcohol Drinking / physiopathology*
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Amygdala / chemistry
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Animals
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Avoidance Learning / physiology*
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Bacterial Proteins / analysis
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Cerebral Cortex / chemistry
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Cerebral Cortex / physiopathology*
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Conditioning, Operant
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Drug Resistance / physiology*
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Ethanol / blood
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Excitatory Amino Acid Antagonists / pharmacology
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Halorhodopsins / analysis
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Luminescent Proteins / analysis
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Male
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Nerve Tissue Proteins / physiology*
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Nucleus Accumbens / physiopathology*
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Optogenetics
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Patch-Clamp Techniques
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Piperidines / pharmacology
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Prefrontal Cortex / chemistry
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Prefrontal Cortex / physiopathology*
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Quinine / pharmacology*
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RNA Interference
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RNA, Small Interfering / pharmacology
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Random Allocation
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Rats
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Rats, Wistar
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / physiology*
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Valine / analogs & derivatives
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Valine / pharmacology
Substances
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Alcohol Deterrents
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Bacterial Proteins
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Excitatory Amino Acid Antagonists
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Grin2d protein, mouse
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Halorhodopsins
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Luminescent Proteins
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NR2B NMDA receptor
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Nerve Tissue Proteins
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Piperidines
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RNA, Small Interfering
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Receptors, N-Methyl-D-Aspartate
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yellow fluorescent protein, Bacteria
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Ethanol
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2-amino-5-phosphopentanoic acid
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Quinine
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Valine
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ifenprodil