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Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction

Molecular Psychiatry volume 26, pages 5277–5285 (2021)Cite this article

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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 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.

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Fig. 1: Proton magnetic resonance spectroscopy (1H-MRS) assessment of glutamate concentration in the nucleus accumbens.
Fig. 2: Craving as a function of cocaine-cue stimulation.
Fig. 3: Impact of cocaine-cue stimulation on glutamate levels within the nucleus accumbens in cocaine addiction.

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Acknowledgements

We thank Johanna Klar, Nathalie Rieser, Martina Riva, and Colette Steinegger for assistance in data collection and Katrin Preller for support with questionnaire programming. This project was supported by a grant from the Zurich Center for Integrative Human Physiology, University of Zurich.

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Authors and Affiliations

  1. Centre for Addictive Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland

    Etna J. E. Engeli, Carlos Nordt, Lea M. Hulka, Matthias Kirschner & Marcus Herdener

  2. Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland

    Niklaus Zoelch, Andreas Hock & Anke Henning

  3. Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland

    Niklaus Zoelch

  4. Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland

    Niklaus Zoelch, Andreas Hock, Milan Scheidegger & Erich Seifritz

  5. Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    Matthias Kirschner

  6. Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, Salerno, Italy

    Fabrizio Esposito

  7. Centre for Forensic Hair Analytics, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland

    Markus R. Baumgartner

  8. Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

    Anke Henning, Erich Seifritz & Boris B. Quednow

  9. Max-Planck-Institute for Biological Cybernetics, Tuebingen, Germany

    Anke Henning

  10. Institute of Physics, Ernst-Moritz-Arndt University, Greifswald, Germany

    Anke Henning

  11. Neuroscience Centre Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland

    Erich Seifritz & Boris B. Quednow

  12. Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland

    Boris B. Quednow

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  1. Etna J. E. Engeli
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Correspondence to Etna J. E. Engeli.

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Unrelated to this study, MH has received speaker fees from Lundbeck, and has served as a consultant for and received research support from Novartis. The other authors declare that they have no conflict of interest.

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Engeli, E.J.E., Zoelch, N., Hock, A. et al. Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction. Mol Psychiatry 26, 5277–5285 (2021). https://doi.org/10.1038/s41380-020-0828-z

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