Arc controls alcohol cue relapse by a central amygdala mechanism

Pagano R 1 , Salamian A 1 , Zielinski J 2 , Beroun A 3 , Nalberczak-Skóra M 1 , Skonieczna E 1 Show all authors , Cały A 1 , Tay N 2 , Banaschewski T 4 , Desrivières S 5 , Grigis A 6 , Garavan H 7 , Heinz A 8 , Brühl R 9 , Martinot JL 10 , Martinot MP 10 , Artiges E 10 , Nees F 4 , Orfanos DP 6 , Poustka L 11 , Hohmann S 4 , Fröhner JH 12 , Smolka MN 12 , Vaidya N 5 , Walter H 8 , Whelan R 13 , IMAGEN consortium , Kalita K 14 , Bito H 15 , Müller CP 16 , Schumann G 17 , Okuno H 18 , Radwanska K 19

Affiliations 

  • 1 Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
  • 2 Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
  • 3 Laboratory of Neuronal Plasticity, BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
  • 4 Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  • 5 Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King's College London, London, UK
  • 6 NeuroSpin, CEA, Université Paris-Saclay, Gif-sur-Yvette, France
  • 7 Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA
  • 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
  • 9 Braunschweig and Berlin, Physikalisch-Technische Bundesanstalt (PTB), Berlin, Germany
  • 10 INSERM U1299 "Trajectoires développementales en psychiatrie, Institut National de la Santé et de la Recherche Médicale, Paris, Gif-sur-Yvette, France
  • 11 Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany
  • 12 Department of Psychiatry, Technische Universität Dresden, Dresden, Germany
  • 13 School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland
  • 14 Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
  • 15 Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  • 16 Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
  • 17 Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany
  • 18 Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
  • 19 Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland. k.radwanska@nencki.edu.pl
Mol Psychiatry, 2023 Feb;28(2):733-745.
PMID: 36357670 DOI: 10.1038/s41380-022-01849-4

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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