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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Asensio S, Romero MJ, Palau C, Sanchez A, Senabre I, Morales JL, et al. Altered neural response of the appetitive emotional system in cocaine addiction: an fMRI Study. Addict Biol. 2010;15:504–16.
Goldstein RZ, Alia-Klein N, Tomasi D, Zhang L, Cottone LA, Maloney T, et al. Is decreased prefrontal cortical sensitivity to monetary reward associated with impaired motivation and self-control in cocaine addiction? Am J Psychiatry. 2007;164:43–51.
Preller KH, Herdener M, Schilbach L, Stämpfli P, Vonmoos M, Ingold N, et al. Functional changes of the reward system underlie blunted response to social gaze in cocaine users. Proc Natl Acad Sci USA. 2014;111:2842–7.
Kirschner M, Sladky R, Haugg A, Stämpfli P, Jehli E, Hodel M, et al. Self-regulation of the dopaminergic reward circuit in cocaine users with mental imagery and neurofeedback. EBioMedicine. 2018;37:489–98.
Haber SN, Knutson B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2009;35:4–26.
Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009;10:561–72.
Lüscher C, Malenka RC. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron. 2011;69:650–63.
Scofield MD, Kalivas PW. Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. Neuroscientist. 2014;20:610–22.
Mulholland PJ, Chandler LJ, Kalivas PW. Signals from the fourth dimension regulate drug relapse. Trends Neurosci. 2016;39:472–85.
McFarland K, Lapish CC, Kalivas PW. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci. 2003;23:3531–7.
Quednow BB, Herdener M. Human pharmacology for addiction medicine: from evidence to clinical recommendations. Prog Brain Res. 2016;224:227–50.
Hulka LM, Scheidegger M, Vonmoos M, Preller KH, Baumgartner MR, Herdener M, et al. Glutamatergic and neurometabolic alterations in chronic cocaine users measured with (1) H-magnetic resonance spectroscopy. Addict Biol. 2014;21:205–17.
Schmaal L, Veltman DJ, Nederveen A, van den Brink W, Goudriaan AE. N-Acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a Randomized Crossover Magnetic Resonance Spectroscopy Study. Neuropsychopharmacology. 2012;37:2143–52.
Yang S, Salmeron BJ, Ross TJ, Xi Z-X, Stein EA, Yang Y. Lower glutamate levels in rostral anterior cingulate of chronic cocaine users—a (1)H-MRS study using TE-averaged PRESS at 3 T with an optimized quantification strategy. Psychiatry Res. 2009;174:171–6.
Martinez D, Slifstein M, Nabulsi N, Grassetti A, Urban NBL, Perez A, et al. Imaging glutamate homeostasis in cocaine addiction with the metabotropic glutamate receptor 5 positron emission tomography radiotracer [(11)C]ABP688 and magnetic resonance spectroscopy. Biol Psychiatry. 2014;75:165–71.
de Graaf RA. In vivo NMR spectroscopy. 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2007.
Neto LL, Oliveira E, Correia F, Ferreira AG. The human nucleus accumbens: where is it? A stereotactic, anatomical and magnetic resonance imaging study. Neuromodulation. 2008;11:13–22.
Dreher W, Leibfritz D. New method for the simultaneous detection of metabolites and water in localized in vivo 1H nuclear magnetic resonance spectroscopy. Magn Reson Med. 2005;54:190–5.
Hock A, MacMillan EL, Fuchs A, Kreis R, Boesiger P, Kollias SS, et al. Non-water-suppressed proton MR spectroscopy improves spectral quality in the human spinal cord. Magn Reson Med. 2012;69:1253–60.
MacMillan EL, Chong DGQ, Dreher W, Henning A, Boesch C, Kreis R. Magnetization exchange with water and T1 relaxation of the downfield resonances in human brain spectra at 3.0 T. Magn Reson Med. 2011;65:1239–46.
Zoelch N, Hock A, Henning A. Quantitative magnetic resonance spectroscopy at 3T based on the principle of reciprocity. NMR Biomed. 2018;55:e3875.
Yagen B, Hernandez O, Bend JR, Cox RH. Synthesis and relative stereochemistry of the four mercapturic acids derived from styrene oxide and N-acetylcysteine. Chem Biol Interact. 1981;34:57–67.
McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM. Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs. 2014;28:95–106.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. American Psychiatric Association Press: Washington, DC, 2000.
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30:672–9.
Friston KJ, Ashburner JT, Kiebel SJ, Nichols TE, Penny WD. Statistical parametric mapping. 1st ed. London: Academic Press; 2006.
Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31:389–94.
Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet. 1991;20:123–34.
Brown H, Prescott R. Applied mixed models in medicine. Chichester, UK: John Wiley & Sons; 2006.
Oz G, Alger JR, Barker PB, Bartha R, Bizzi A, Boesch C, et al. Clinical proton MR spectroscopy in central nervous system disorders. Radiology. 2014;270:658–79.
Knackstedt LA, Melendez RI, Kalivas PW. Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry. 2010;67:81–84.
Trantham-Davidson H, LaLumiere RT, Reissner KJ, Kalivas PW, Knackstedt LA. Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training. J Neurosci. 2012;32:12406–10.
Reissner KJ, Gipson CD, Tran PK, Knackstedt LA, Scofield MD, Kalivas PW. Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement. Addict Biol. 2015;20:316–23.
Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci. 2005;25:6389–93.
Bowers MS, McFarland K, Lake RW, Peterson YK, Lapish CC, Gregory ML, et al. Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking. Neuron. 2004;42:269–81.
Zaehle T, Bauch EM, Hinrichs H, Schmitt FC, Voges J, Heinze H-J, et al. Nucleus accumbens activity dissociates different forms of salience: evidence from human intracranial recordings. J Neurosci. 2013;33:8764–71.
Léna I, Parrot S, Deschaux O, Muffat-Joly S, Sauvinet V, Renaud B, et al. Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep-wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. J Neurosci Res. 2005;81:891–9.
Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev. 1993;18:247–91.
Batten SR, Pomerleau F, Quintero J, Gerhardt GA, Beckmann JS. The role of glutamate signaling in incentive salience: second-by-second glutamate recordings in awake Sprague-Dawley rats. J Neurochem. 2018;145:276–86.
O’Gorman Tuura R, Warnock G, Ametamey S, Treyer V, Noeske R, Buck A, et al. Imaging glutamate redistribution after acute N-acetylcysteine administration: a simultaneous PET/MR study. NeuroImage. 2019;184:826–33.
Schulte MHJ, Wiers RW, Boendermaker WJ, Goudriaan AE, van den Brink W, van Deursen DS, et al. The effect of N-acetylcysteine and working memory training on cocaine use, craving and inhibition in regular cocaine users: correspondence of lab assessments and Ecological Momentary Assessment. Addict Behav. 2017;79:24–31.
Womersley JS, Townsend DM, Kalivas PW, Uys JD. Targeting redox regulation to treat substance use disorder using N-acetylcysteine. Eur J Neurosci. 2019;50:2538–51.
Olive MF, Cleva RM, Kalivas PW, Malcolm RJ. Glutamatergic medications for the treatment of drug and behavioral addictions. Pharm Biochem Behav. 2012;100:801–10.
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.
Conflict of interest
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