# The glucocorticoid receptor as a mechanism of top-down control of cue-motivated behavior

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $195,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The glucocorticoid receptor (GR) is best known for its role in mediating the stress response. Thus, it is not
surprising that this receptor has been implicated in the pathophysiology of several psychiatric disorders.
Recently, a number of reports have emerged identifying GR-related polymorphisms associated with
susceptibility to cocaine use and addiction. Indeed, it has been known for decades that glucocorticoids, via GR,
interact with dopamine to produce individual differences in response to drugs of abuse. The mechanism by
which this occurs, however, remains to be determined. Importantly, while stress can facilitate dopamine-
glucocorticoid interactions, it is not necessary. That is, an individual may be inherently “wired”, or primed for
these interactions to occur, rendering them more susceptible to addiction, even in the absence of stress. The
overarching goal of the proposed work is to identify one such priming mechanism. Some individuals may be
particularly prone to addiction because they have a tendency to attribute drug cues with excessive incentive
motivational value. For these individual exposure to cues (e.g. paraphernalia) previously associated with drug-
taking may precipitate relapse, despite a desire to remain abstinent. In rats, we have shown that those with an
increase propensity for incentive learning have insufficient “top-down” cortical control, concurrent with
hyperactive subcortical mechanisms. In conjunction, these rats are more impulsive, have deficits in attentional
control and are more likely to exhibit cue-induced reinstatement of drug-seeking behavior (i.e. relapse). The
neurobehavioral endophenotype captured by the propensity to attribute incentive salience to reward cues,
therefore, is reminiscent of individuals with addiction. The central hypothesis to be tested here is that GR
function in a “top-down” cortico-striatal circuit plays a critical role in determining this addiction-related
endophenotype. We will take advantage of CRISPR (Clustered Regularly Interspaced Short Palindromic
Repeats)/Cas 9-mediated gene-editing technology to selectively manipulate GR in glutamatergic afferents
projecting from the prelimbic cortex (PrL) to the nucleus accumbens core (NAcC) - a circuit that we believe has
little to do with stress responsivity and more to do with mediating responses to reward-associated cues. We
hypothesize that knockdown of GR selectively in this cortico-striatal circuit will attenuate 1) the propensity to
attribute incentive motivational value to a reward cue, and 2) cue-induced reinstatement of cocaine-seeking
behavior. This exploratory grant has the potential to uncover a novel neural mechanism that contributes to the
propensity for relapse. Regardless of the outcome, this research will set a foundation for future studies to
further investigate the role of GR in addiction-related behaviors with great neuroanatomical precision.

## Key facts

- **NIH application ID:** 10105502
- **Project number:** 1R21DA052594-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Shelly Beth Flagel
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $195,000
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105502

## Citation

> US National Institutes of Health, RePORTER application 10105502, The glucocorticoid receptor as a mechanism of top-down control of cue-motivated behavior (1R21DA052594-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105502. Licensed CC0.

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