# Glutamatergic adaptation to stress as a mechanism for anhedonia and treatment response with ketamine

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $749,372

## Abstract

Project Summary/Abstract
Anhedonia in patients with major depressive disorder (MDD) frequently fails to respond to available
psychosocial and pharmacological treatments and has been robustly linked to marked disability as well as
suicidal risk. A well-validated model of anhedonia suggests that anhedonia may result from prolonged
exposure to stress (i.e. “stress-induced anhedonia”) as manifested by chronic behavioral inhibition and a failure
to pursue rewards. One proposed mechanism of stress-induced anhedonia is alteration of glutamate function
in medial prefrontal cortex (mPFC). To investigate this hypothesis in humans, we recently conducted a series
of studies using single-voxel MR spectroscopy measures of glutamate in mPFC before and after an acute
stress challenge. We found that mPFC glutamate increased in healthy controls with low levels of stress, but
decreased glutamate responses in controls with high levels of stress. Interestingly, in unmedicated MDD
patients, we found no change or an increase in mPFC glutamate following stress. This altered mPFC
glutamate response to stress in MDD patients was in turn correlated with negative expectations of future
events and thus may be a mechanism by which chronic stress is translated into impaired reward valuation and
reduced motivation. Consistent with this notion, the NMDA receptor antagonist ketamine has been shown to
improve anhedonic symptoms in both pre-clinical and clinical studies. Nevertheless, the role of mPFC and
other regions in this altered glutamate stress response in MDD or its association with RDoC positive valence
constructs that underlie anhedonia has yet to be fully established. Moreover, whether reversal of this altered
glutamate response in MDD underlies the effects of ketamine on anhedonia is unknown. Thus, the current
proposal seeks to use whole-brain multi-modal 3D ultrahigh resolution spectroscopic MRI (SMRI) and fMRI
assessments of RDoC constructs related to reward valuation and motivation to examine glutamate responses
to stress and its relationship with symptoms and neurocognitive correlates of anhedonia before and after a
ketamine challenge in MDD patients. We will use a novel SMRI sequence to measure glutamate before and
after an acute stressor and a no-stress control in 60 healthy controls and 80 MDD patients. After baseline
scanning, MDD patients will be randomized to receive a single dose of intravenous ketamine or placebo, and
complete follow-up scans at 24-hours and 2 weeks. By establishing an altered glutamate response to stress as
a mechanism for anhedonic effects of chronic stress and its reversal by ketamine, these data will be able to
serve as a drug discovery platform for other pharmacologic agents targeting the glutamate system to treat
stress-induced anhedonia.

## Key facts

- **NIH application ID:** 10755745
- **Project number:** 5R01MH126083-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Michael Tilghman Treadway
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $749,372
- **Award type:** 5
- **Project period:** 2022-03-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755745

## Citation

> US National Institutes of Health, RePORTER application 10755745, Glutamatergic adaptation to stress as a mechanism for anhedonia and treatment response with ketamine (5R01MH126083-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755745. Licensed CC0.

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