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

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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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Figure 1: Inhibition of NMDARs in the NAcore reduced aversion-resistant alcohol intake.
Figure 2: Halorhodopsin inhibition of mPFC- and INS-to-NAcore inputs reduced quinine-resistant alcohol intake.
Figure 3: Halorhodopsin inhibition of mPFC- and INS-to-NAcore inputs reduced footshock-resistant alcohol intake.
Figure 4: NAcore neurons from alcohol-drinking rats showed hyperpolarization-active NMDARs under mPFC-to-NAcore inputs.
Figure 5: NAcore neurons from alcohol-drinking rats showed hyperpolarization-active NMDARs under mPFC and INS but not BLA inputs to the NAcore.
Figure 6: NMDARs regulate evoked action potential firing under mPFC-to-NAcore inputs from alcohol-drinking but not naive rats.
Figure 7: Grin2c but not Grin2d or Grin2b subunits mediate hyperpolarization-active NMDARs under mPFC-to-NAcore terminals and promote quinine-resistant alcohol intake.

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Acknowledgements

We thank V. Kharazia and the Gallo Center P50 National Institute on Alcohol Abuse and Alcoholism (NIAAA) AA017072 Histology Core for assistance with histology and R. Maiya for shRNA assistance. Supported by NIAAA RO1AA015358 (F.W.H.), National Institute on Drug Abuse F32DA028065 (T.S.), NIAAA/NIH RO1A/MH13438 (D.R.) and funds provided by the State of California for medical research for alcohol substance abuse through the University of California San Francisco (D.R., A.B., R.O.M.).

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T.S., B.T.C., D.R., R.O.M., A.B. and F.W.H. designed experiments. T.S., S.-J.C., J.A.S., S.L.G. and F.W.H. collected and analyzed data. S.L.G., J.D., B.T.C., B.K.H., D.R. and R.O.M. generated and tested NMDAR shRNAs. T.S., F.W.H. and R.O.M. wrote the paper.

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Correspondence to Antonello Bonci or F Woodward Hopf.

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The authors declare no competing financial interests.

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Seif, T., Chang, SJ., Simms, J. et al. Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. Nat Neurosci 16, 1094–1100 (2013). https://doi.org/10.1038/nn.3445

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