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Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction


Engeli, Etna J E; Zoelch, Niklaus; Hock, Andreas; Nordt, Carlos; Hulka, Lea M; Kirschner, Matthias; Scheidegger, Milan; Esposito, Fabrizio; Baumgartner, Markus R; Henning, Anke; Seifritz, Erich; Quednow, Boris B; Herdener, Marcus (2021). Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction. Molecular Psychiatry, 26(9):5277-5285.

Abstract

Cocaine addiction is characterized by overwhelming craving for the substance, which drives its escalating use despite adverse consequences. Animal models suggest a disrupted glutamate homeostasis in the nucleus accumbens to underlie addiction-like behaviour. After chronic administration of cocaine, rodents show decreased levels of accumbal glutamate, whereas drug-seeking reinstatement is associated with enhanced glutamatergic transmission. However, due to technical obstacles, the role of disturbed glutamate homeostasis for cocaine addiction in humans remains only partially understood, and accordingly, no approved pharmacotherapy exists. Here, we applied a tailored proton magnetic resonance spectroscopy protocol that allows glutamate quantification within the human nucleus accumbens. We found significantly reduced basal glutamate concentrations in the nucleus accumbens in cocaine-addicted (N = 26) compared to healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared to baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on two days). Taken together, our findings reveal a disturbed accumbal glutamate homeostasis as a key neurometabolic feature of cocaine addiction also in humans. Therefore, we suggest the glutamatergic system as a promising target for the development of novel pharmacotherapies, and in addition, as a potential biomarker for a personalised medicine approach in addiction.

Abstract

Cocaine addiction is characterized by overwhelming craving for the substance, which drives its escalating use despite adverse consequences. Animal models suggest a disrupted glutamate homeostasis in the nucleus accumbens to underlie addiction-like behaviour. After chronic administration of cocaine, rodents show decreased levels of accumbal glutamate, whereas drug-seeking reinstatement is associated with enhanced glutamatergic transmission. However, due to technical obstacles, the role of disturbed glutamate homeostasis for cocaine addiction in humans remains only partially understood, and accordingly, no approved pharmacotherapy exists. Here, we applied a tailored proton magnetic resonance spectroscopy protocol that allows glutamate quantification within the human nucleus accumbens. We found significantly reduced basal glutamate concentrations in the nucleus accumbens in cocaine-addicted (N = 26) compared to healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared to baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on two days). Taken together, our findings reveal a disturbed accumbal glutamate homeostasis as a key neurometabolic feature of cocaine addiction also in humans. Therefore, we suggest the glutamatergic system as a promising target for the development of novel pharmacotherapies, and in addition, as a potential biomarker for a personalised medicine approach in addiction.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
04 Faculty of Medicine > Neuroscience Center Zurich
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > Institute of Legal Medicine
04 Faculty of Medicine > Institute of Biomedical Engineering
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Biology
Life Sciences > Cellular and Molecular Neuroscience
Health Sciences > Psychiatry and Mental Health
Uncontrolled Keywords:Molecular Biology, Cellular and Molecular Neuroscience, Psychiatry and Mental health
Language:English
Date:1 September 2021
Deposited On:02 Jul 2020 15:30
Last Modified:27 Jan 2022 02:09
Publisher:Nature Publishing Group
ISSN:1359-4184
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41380-020-0828-z
PubMed ID:32601455

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