Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction

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 behavior. After chronic administration of cocaine, r...

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Bibliographic Details
Published in:Molecular psychiatry 2021-09, Vol.26 (9), p.5277-5285
Main Authors: 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
Format: Article
Language:English
Subjects:
Acetylcysteine
Addictions
Animal models
Animals
Cocaine
Cocaine abuse
Cocaine-Related Disorders - drug therapy
Complications and side effects
Development and progression
Drug therapy
Drug-Seeking Behavior
Glutamate
Glutamatergic transmission
Glutamic Acid
Health aspects
Homeostasis
Humans
Magnetic resonance spectroscopy
Nucleus Accumbens
Physiological aspects
Precision medicine
Reinstatement
Self Administration
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Summary: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 behavior. 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 with healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared with baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on 2 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 personalized medicine approach in addiction.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-020-0828-z