# Thorase Regulation of the Actions of Cocaine

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2020 · $376,721

## Abstract

Thorase Regulation of the Actions of Cocaine
 Addiction to drugs of abuse such as cocaine is a world-wide health crisis. In the USA there are an
estimated 1.5 million current cocaine users, a number that has been relatively stable. Extensive studies have
revealed that cocaine, induces plastic changes in the brain that underlie the behavioral changes including
changes in expression of AMPA receptors as well as activation of the mechanistic target of rapamycin
complex 1 (mTORC1) in the onset and maintenance of cocaine addiction. We discovered Thorase, an AAA+
ATPases that serves to facilitate the disassembly AMPA receptors and recently discovered it also
disassembles mTORC1. Our hypothesis is that Thorase is poised to play a pivotal and critical role in the
behavioral and cellular responses to cocaine by directing both AMPA receptor expression and mTORC1
activity and thus underlies important changes in dopaminergic neuroplasticity which we will explore in the
following Aims.
Aim 1: In order to fully comprehend the actions of cocaine on Thorase and mTOR signaling the functional
and biochemical interactions of Thorase with mTOR and components of mTORC1 will be explored and
defined.
Aim 2: The role of Thorase activity on cocaine’s reinforcing properties will be studied. Self-administration and
reinstatement to cocaine seeking behavior will be monitored in wild type, Thorase KO and Thorase TG mice.
Aim 3: As Rapamycin blocks cocaine induced behaviors in rodents, it is reasonable to predict that cocaine is
hyperactivating mTORC1. Since inhibition or genetic deletion of nNOS, and thus NO, has similar effects on
cocaine behaviors as rapamycin, and S-nitrosylation inhibits Thorase activity, we hypothesize that cocaine is
inhibiting Thorase through S-nitrosylation resulting in hyperactivation of mTORC1 and altering expression of
AMPA receptors.
Aim 4: Will address whether mTORC1 and Thorase are largely responsible for the proteomic and
translational changes following exposure to cocaine. Changes to the transcriptome, translatome and
proteome in response to cocaine exposure will be explored.
 The overarching goal of this project is to define the role of Thorase in the regulation of neuroplastic
responses that underlie the addictive behaviors to cocaine.

## Key facts

- **NIH application ID:** 9932396
- **Project number:** 5P50DA044123-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** VALINA L. DAWSON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,721
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932396

## Citation

> US National Institutes of Health, RePORTER application 9932396, Thorase Regulation of the Actions of Cocaine (5P50DA044123-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932396. Licensed CC0.

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