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Arc controls alcohol cue relapse by a central amygdala mechanism

Molecular Psychiatry volume 28, pages 733–745 (2023)Cite this article

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A Correction to this article was published on 05 December 2022

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Abstract

Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention.

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Fig. 1: AUD-related behaviors in ArcKO mice.
Fig. 2: Arc protein is upregulated in the CeA during cue relapse.
Fig. 3: Alcohol consumption decreases Arc gene methylation and increases Arc mRNA expression in the mouse amygdala.
Fig. 4: Downregulation of Arc in CeM increases motivation and alcohol seeking during relapse induced by alcohol-predicting cues.
Fig. 5: Arc regulates synaptic strength of BLA → CeM pathway during cue relapse.
Fig. 6: Alcohol consumption affects ARC gene methylation.

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Acknowledgements

This work has been supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no 665735 (Bio4Med) and by the funding from Polish Ministry of Science and Higher Education within 2016-2020 funds for the implementation of international projects (agreement no 3548/H2020/COFUND/2016/2) and National Science Center (Poland) Harmonia and Opus grants (UMO-2016/22/M/NZ4/00674 and UMO-2015/19/B/NZ4/03163) to KR. This work was further supported by the German National Science Foundation (Deutsche Forschungsgemeinschaft [DFG]), grant MU 2789/8–2 and in part by the Federal Ministry of Education and Research (BMBF) under the e:Med Program (031L0190B and 01KC2004B) and by Japan Society for the Promotion of Science KAKENHI grants (17H06312 and 19H03328). This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT—2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), Human Brain Project (HBP SGA 2, 785907, and HBP SGA 3, 945539), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute of Health (NIH) (R01DA049238, A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers), the National Institute for Health Research (NIHR) Biomedical Research Center at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B; Forschungsnetz IMAC-Mind 01GL1745B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01), NSFC grant 82150710554 and environMENTAL grant. Further support was provided by grants from:—the ANR (ANR-12-SAMA-0004, AAPG2019—GeBra), the Eranet Neuron (AF12-NEUR0008-01—WM2NA; and ANR-18-NEUR00002-01-ADORe), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), U.S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1) and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence. ImagenPathways “Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways” is a collaborative project supported by the European Research Area Network on Illicit Drugs (ERANID). This paper is based on independent research commissioned and funded in England by the National Institute for Health Research (NIHR) Policy Research Program (project ref. PR-ST-0416-10001. The views expressed in this article are those of the authors and not necessarily those of the national funding agencies or ERANID.

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Author notes

  1. These authors contributed equally: Christian P. Müller, Gunter Schumann, Hiroyuki Okuno, Kasia Radwanska.

Authors and Affiliations

  1. Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland

    Roberto Pagano, Ahmad Salamian, Maria Nalberczak-Skóra, Edyta Skonieczna, Anna Cały & Kasia Radwanska

  2. Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Janusz Zielinski & Nicole Tay

  3. Laboratory of Neuronal Plasticity, BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland

    Anna Beroun

  4. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Tobias Banaschewski, Frauke Nees & Sarah Hohmann

  5. Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King’s College London, London, UK

    Sylvane Desrivières & Nilakshi Vaidya

  6. NeuroSpin, CEA, Université Paris-Saclay, Gif-sur-Yvette, France

    Antoine Grigis & Dimitri Papadopoulos Orfanos

  7. Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA

    Hugh Garavan

  8. Department of Psychiatry and Psychotherapy, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany

    Andreas Heinz & Henrik Walter

  9. Braunschweig and Berlin, Physikalisch-Technische Bundesanstalt (PTB), Berlin, Germany

    Rüdiger Brühl

  10. INSERM U1299 “Trajectoires développementales en psychiatrie, Institut National de la Santé et de la Recherche Médicale, Paris, Gif-sur-Yvette, France

    Jean-Luc Martinot, Marie-Laure Paillère Martinot & Eric Artiges

  11. AP-HP. Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France

    Jean-Luc Martinot, Marie-Laure Paillère Martinot & Eric Artiges

  12. Psychiatry Department, EPS Barthélémy Durand, Etampes, France

    Jean-Luc Martinot, Marie-Laure Paillère Martinot & Eric Artiges

  13. Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Université Paris-Saclay, Paris, Gif-sur-Yvette, France

    Jean-Luc Martinot, Marie-Laure Paillère Martinot & Eric Artiges

  14. Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany

    Frauke Nees

  15. Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany

    Luise Poustka

  16. Department of Psychiatry, Technische Universität Dresden, Dresden, Germany

    Juliane H. Fröhner & Michael N. Smolka

  17. School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland

    Robert Whelan

  18. Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Haruhiko Bito

  19. Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany

    Gunter Schumann

  20. Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland

    Katarzyna Kalita

  21. Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany

    Christian P. Müller

  22. Centre for Drug Research, Universiti Sains Malaysia, Minden, Penang, Malaysia

    Christian P. Müller

  23. Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China

    Gunter Schumann

  24. Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

    Hiroyuki Okuno

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  1. Roberto Pagano
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  29. Christian P. Müller
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  31. Hiroyuki Okuno
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Consortia

IMAGEN consortium

  • Tobias Banaschewski
  • , Sylvane Desrivières
  • , Antoine Grigis
  • , Hugh Garavan
  • , Andreas Heinz
  • , Rüdiger Brühl
  • , Jean-Luc Martinot
  • , Marie-Laure Paillère Martinot
  • , Eric Artiges
  • , Frauke Nees
  • , Dimitri Papadopoulos Orfanos
  • , Luise Poustka
  • , Sarah Hohmann
  • , Juliane H. Fröhner
  • , Michael N. Smolka
  • , Nilakshi Vaidya
  • , Henrik Walter
  • , Robert Whelan
  •  & Gunter Schumann

Contributions

KR initiated the studies, designed experiments, supervised and coordinated research; RP, AS, ES, AB, MNS, AC and KR performed and analyzed mouse studies; HO, HB and KK provided materials and supervised in vitro experiments; IMAGEN consortium, NT, JZ, GS and CPM analyzed human data. RP, CPM, GS and KR wrote the paper. All authors discussed the results and commented on the paper.

Corresponding author

Correspondence to Kasia Radwanska.

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Competing interests

TB served in an advisory or consultancy role for eye level, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker’s fee by Janssen, Medice and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. Dr Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. LP served in an advisory or consultancy role for Roche and Viforpharm and received a speaker’s fee from Shire. She received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships. The other authors report no biomedical financial interests or potential competing interests.

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The original online version of this article was revised: In Table 1 of this article, the columns are wrongly labelled in a published pdf file. They should be labelled as in the below. The original article has been corrected.

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Pagano, R., Salamian, A., Zielinski, J. et al. Arc controls alcohol cue relapse by a central amygdala mechanism. Mol Psychiatry 28, 733–745 (2023). https://doi.org/10.1038/s41380-022-01849-4

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  • DOI: https://doi.org/10.1038/s41380-022-01849-4

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