Arc controls alcohol cue relapse by a central amygdala mechanism

Roberto Pagano¹, Ahmad Salamian¹, Janusz Zielinski², Anna Beroun³, Maria Nalberczak-Skóra¹, Edyta Skonieczna¹, Anna Cały¹, Nicole Tay², Tobias Banaschewski⁴, Sylvane Desrivières⁵, Antoine Grigis⁶, Hugh Garavan⁷, Andreas Heinz⁸, Rüdiger Brühl⁹, Jean-Luc Martinot^{10

11

12

13}, Marie-Laure Paillère Martinot^{10

11

12

13}, Eric Artiges^{10

11

12

13}, Frauke Nees^{4

14}, Dimitri Papadopoulos Orfanos⁶, Luise Poustka¹⁵, Sarah Hohmann⁴, Juliane H Fröhner¹⁶, Michael N Smolka¹⁶, Nilakshi Vaidya⁵, Henrik Walter⁸, Robert Whelan¹⁷; IMAGEN consortium; Katarzyna Kalita¹⁸, Haruhiko Bito¹⁹, Christian P Müller^#^{20

21}, Gunter Schumann^#^{22

23}, Hiroyuki Okuno^#²⁴, Kasia Radwanska^#²⁵

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 AP-HP. Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France.
¹² Psychiatry Department, EPS Barthélémy Durand, Etampes, France.
¹³ Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Université Paris-Saclay, Paris, Gif-sur-Yvette, France.
¹⁴ Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany.
¹⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany.
¹⁶ Department of Psychiatry, Technische Universität Dresden, Dresden, Germany.
¹⁷ School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
¹⁸ Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
¹⁹ Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²⁰ Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
²¹ Centre for Drug Research, Universiti Sains Malaysia, Minden, Penang, Malaysia.
²² Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.
²³ Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China.
²⁴ Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
²⁵ Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland. k.radwanska@nencki.edu.pl.

^# Contributed equally.

PMID: 36357670
DOI: 10.1038/s41380-022-01849-4

Arc controls alcohol cue relapse by a central amygdala mechanism

Roberto Pagano et al. Mol Psychiatry. 2023 Feb.

. 2023 Feb;28(2):733-745.

doi: 10.1038/s41380-022-01849-4. Epub 2022 Nov 10.

Authors

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 AP-HP. Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France.
¹² Psychiatry Department, EPS Barthélémy Durand, Etampes, France.
¹³ Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Université Paris-Saclay, Paris, Gif-sur-Yvette, France.
¹⁴ Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany.
¹⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany.
¹⁶ Department of Psychiatry, Technische Universität Dresden, Dresden, Germany.
¹⁷ School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
¹⁸ Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
¹⁹ Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²⁰ Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
²¹ Centre for Drug Research, Universiti Sains Malaysia, Minden, Penang, Malaysia.
²² Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.
²³ Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China.
²⁴ Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
²⁵ Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland. k.radwanska@nencki.edu.pl.

^# Contributed equally.

PMID: 36357670
DOI: 10.1038/s41380-022-01849-4

Erratum in

Correction: Arc controls alcohol cue relapse by a central amygdala mechanism.
Pagano R, Salamian A, Zielinski J, Beroun A, Nalberczak-Skóra M, Skonieczna E, Cały A, Tay N, Banaschewski T, Desrivières S, Grigis A, Garavan H, Heinz A, Brühl R, Martinot JL, Martinot MP, Artiges E, Nees F, Orfanos DP, Poustka L, Hohmann S, Fröhner JH, Smolka MN, Vaidya N, Walter H, Whelan R; IMAGEN consortium*; Kalita K, Bito H, Müller CP, Schumann G, Okuno H, Radwanska K. Pagano R, et al. Mol Psychiatry. 2024 Jan;29(1):5. doi: 10.1038/s41380-022-01895-y. Mol Psychiatry. 2024. PMID: 36471124 No abstract available.

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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References

1. American Psychiatric Association, American Psychiatric Association, editors. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, D.C: American Psychiatric Association; 2013.
1. Carvalho AF, Heilig M, Perez A, Probst C, Rehm J. Alcohol use disorders. Lancet. 2019;394:781–92. - DOI
1. Sinha R. How does stress lead to risk of alcohol relapse? Alcohol Res. 2012;34:432–40.
1. Sinha R, Li CSR. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev. 2007;26:25–31. - DOI
1. Venniro M, Caprioli D, Shaham Y Animal models of drug relapse and craving. Progress in Brain Research, vol. 224, Elsevier; 2016. p. 25–52.

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Arc controls alcohol cue relapse by a central amygdala mechanism

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Arc controls alcohol cue relapse by a central amygdala mechanism

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