mTORC1 in the orbitofrontal cortex promotes habitual alcohol seeking

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Cite this article as: eLife 2019;8:e51333 doi: 10.7554/eLife.51333

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Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in dendritic translation and in learning and memory. We previously showed that heavy alcohol use activates mTORC1 in the orbitofrontal cortex (OFC) of rodents (1). Here, we set out to determine the consequences of alcohol-dependent mTORC1 activation in the OFC. We found that inhibition of mTORC1 activity attenuates alcohol seeking and restores sensitivity to outcome devaluation in rats that habitually seek alcohol. In contrast, habitual responding for sucrose was unaltered by mTORC1 inhibition, suggesting that mTORC1's role in habitual behavior is specific to alcohol. We further show that inhibition of GluN2B in the OFC attenuates alcohol-dependent mTORC1 activation, alcohol seeking and habitual responding for alcohol. Together, these data suggest that the GluN2B/mTORC1 axis in the OFC drives alcohol seeking and habit.

Article and author information

Author details

Nadege Morisot

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Khanhky Phamluong

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Yann Ehinger

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Anthony L Berger

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Jeffrey J Moffat

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Dorit Ron

Department of Neurology, University of California, San Francisco, San Francisco, United States

For correspondence
dorit.ron@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5161-967X

Funding

National Institute on Alcohol Abuse and Alcoholism (P50 AA017072)

Dorit Ron

National Institute on Alcohol Abuse and Alcoholism (R01 AA027474)

Dorit Ron

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were approved by the University of California San Francisco Institutional Animal Care and Use Committee (IACUC) and were conducted in agreement with the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).(protocol number number AN179720-01B),

Reviewing Editor

Mary Kay Lobo, University of Maryland, United States

Publication history

Received: August 25, 2019
Accepted: December 9, 2019
Accepted Manuscript published: December 10, 2019 (version 1)
Accepted Manuscript updated: December 11, 2019 (version 2)
Version of Record published: January 14, 2020 (version 3)

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.