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Articles, Cellular/Molecular

The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons

Jacob T. Beckley, Sophie Laguesse, Khanhky Phamluong, Nadege Morisot, Scott A. Wegner and Dorit Ron
Journal of Neuroscience 20 January 2016, 36 (3) 701-713; DOI: https://doi.org/10.1523/JNEUROSCI.2254-15.2016
Jacob T. Beckley
Department of Neurology, University of California, San Francisco, California 94143-0663
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Sophie Laguesse
Department of Neurology, University of California, San Francisco, California 94143-0663
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Khanhky Phamluong
Department of Neurology, University of California, San Francisco, California 94143-0663
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Nadege Morisot
Department of Neurology, University of California, San Francisco, California 94143-0663
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Scott A. Wegner
Department of Neurology, University of California, San Francisco, California 94143-0663
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Dorit Ron
Department of Neurology, University of California, San Francisco, California 94143-0663
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This article has corrections. Please see:

  • Correction: Beckley et al., The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neuron - April 13, 2016
  • Erratum: Beckley et al., “The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons” - September 09, 2022

Abstract

Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake.

SIGNIFICANCE STATEMENT Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons, which is dependent on D1R and mTORC1. We also find that mTORC1 is necessary for the sustained alcohol consumption and preference across the initial drinking sessions. The first alcohol binge activates mTORC1 in NAc D1+ neurons and increases levels of synaptic proteins involved in glutamatergic signaling. Thus, the D1R/mTORC1-dependent plasticity following the first alcohol exposure may be a critical cellular component of reinforcement learning.

  • addiction
  • alcohol
  • dopamine
  • mTOR
  • plasticity
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The Journal of Neuroscience: 36 (3)
Journal of Neuroscience
Vol. 36, Issue 3
20 Jan 2016
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The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons
Jacob T. Beckley, Sophie Laguesse, Khanhky Phamluong, Nadege Morisot, Scott A. Wegner, Dorit Ron
Journal of Neuroscience 20 January 2016, 36 (3) 701-713; DOI: 10.1523/JNEUROSCI.2254-15.2016

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The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons
Jacob T. Beckley, Sophie Laguesse, Khanhky Phamluong, Nadege Morisot, Scott A. Wegner, Dorit Ron
Journal of Neuroscience 20 January 2016, 36 (3) 701-713; DOI: 10.1523/JNEUROSCI.2254-15.2016
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Keywords

  • addiction
  • alcohol
  • dopamine
  • mTOR
  • plasticity

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