# mTOR Signaling and Alcohol Use Disorder

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $327,477

## Abstract

The mammalian target of rapamycin in complex 1 (mTORC1) is a kinase that plays a key role in protein
translation at dendrites, synaptic plasticity, and learning and memory. We discovered that mTORC1 plays a
major role in behaviors associated with alcohol abuse disorders (AUD) including excessive alcohol seeking
and intake, as well as memories associated with alcohol reward. We further found that mTORC1
contributes to synaptic and structural plasticity in the nucleus accumbens via the translation of synaptic
proteins. More recently we found that repeated cycles of alcohol binge drinking and withdrawal activate
mTORC1 signaling in the Orbitofrontal Cortex (OFC), a brain region important for associative learning and
reward value. We further showed that inhibition of mTORC1 in the OFC of rats attenuates alcohol seeking
and habitual alcohol responding. Finally, we generated data suggesting that NMDA receptors (NMDAR) in
the OFC participate in mTORC1 activation and alcohol seeking and habit. The OFC receives glutamatergic
inputs from the basolateral amygdala (BLA) and mediodorsal thalamic nucleus (MDmc), and projects to
the dorsal striatum (DS), and the BLA. We hypothesize that recruitment of glutamatergic BLA and/or
MDmc neurons in response to alcohol activates mTORC1 signaling in the OFC to drive habitual alcohol
seeking (Aim 1). We further hypothesize that mTORC1 is activated by alcohol in specific OFC projecting
neurons to initiate alcohol seeking and habitual responding (Aim 2). In Aim 3, we will determine the
molecular mechanisms underlying the aforementioned behavioral outcomes. Specifically, we will study the
contribution of the mTORC1 downstream target, collapsin response mediator protein II (CRMP-2), to
alcohol seeking and habit. We will also conduct an RNA sequencing analysis to identify novel downstream
targets of mTORC1 in the OFC whose translation is increased by alcohol. To address these hypotheses,
and test the contribution of the mTORC1 signaling in the context of OFC circuitries, we plan to use
novel molecular tools in combination with behavioral paradigms in rats. Together, this research proposal
will allow us for the first time, to elucidate the role of an important molecular target of alcohol in the context
of key neural circuits. Furthermore, the contribution of the OFC to AUD has been understudied, and our
research effort will greatly expand the knowledge on this topic. Finally, our studies on mTORC1 and its
downstream targets will contribute to drug development efforts for the treatment of AUD.
RELEVANCE (See instructions):
This proposal is aimed to study how the kinase mTORC1 in brain circuitries that centers around the brain
region, OFC, contributes to two clinically relevant phenotypes, alcohol seeking and habit. To do so, we will
use state of the art molecular approaches in combination with behavioral paradigms in rats. Our study will
not only expand our knowledge on the neuroadaptations that underlie alcohol actions in the ...

## Key facts

- **NIH application ID:** 9964609
- **Project number:** 5R01AA027474-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** DORIT RON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $327,477
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964609

## Citation

> US National Institutes of Health, RePORTER application 9964609, mTOR Signaling and Alcohol Use Disorder (5R01AA027474-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9964609. Licensed CC0.

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