# Evaluation of pharmacologically-induced changes in excitatory glutamatergic neurotransmission of severe TBI patients

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $211,875

## Abstract

Project Summary
Studies in patients with disorders of consciousness (DOC) after severe brain injury implicate dysfunction of
the anterior forebrain mesocircuit dysfunction a key underlying mechanism. The anterior forebrain
metabolism in DOC is markedly downregulated across brain regions underpinning highly elaborated
cognitive behaviors demonstrating a collapse of the level of synaptic background activity required for
consistent goal-directed behavior and arousal regulation. Since dopamine levels are one of the primary
controllers of the level of synaptic background activity within these forebrain structures and in regulating
excitatory glutamatergic homeostasis, we propose to investigate the specific contribution of presynaptic
dopamine function in glutamatergic neurotransmission in posttraumatic DOC. The aim of the present
study is to measure metabotropic glutamate receptors 5 occupancy in the main glutamatergic structures of
the brain using [18F]FPEB-PET at rest and following a short pharmacological challenge with amantadine, an
NMDA-R antagonist, following L-DOPA, and amantadine + L-DOPA. Using this novel technique in DOC we
will characterize the relevance of a presynaptic deficiency to synthesize and/or release dopamine in
the final regulation of excitatory interneurons of the anterior forebrain mesocircuit.
It is unknown whether glutamatergic neurotransmission is affected across the population of subjects with
DOC and, if this condition is secondary to a presynaptic dopaminergic failure of the anterior forebrain
mesocircuit (i.e., down-regulation). Since we previously identified the existence of a presynaptic
dopaminergic deficit in these subjects due to a failure in the biosynthesis of dopamine, we will evaluate
if by providing the main biological substrate of the biosynthesis process (i.e., L-DOPA) the glutamatergic
system regains homeostasis. We therefore propose to investigate patients with posttraumatic DOC using
[18F]FPEB-PET at rest and following short pharmacological challenges aimed at increasing glutamate and
dopamine release.

## Key facts

- **NIH application ID:** 10136124
- **Project number:** 5R21NS109697-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Esteban Andres Fridman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $211,875
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136124

## Citation

> US National Institutes of Health, RePORTER application 10136124, Evaluation of pharmacologically-induced changes in excitatory glutamatergic neurotransmission of severe TBI patients (5R21NS109697-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136124. Licensed CC0.

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