Arc controls alcohol cue relapse by a central amygdala mechanism

Molecular psychiatry

Mol Psychiatry. 2022 Nov 10. doi: 10.1038/s41380-022-01849-4. Online ahead of print.

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.

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

Authors

Roberto Pagano
Ahmad Salamian
Janusz Zielinski
Anna Beroun
Maria Nalberczak-Skóra
Edyta Skonieczna
Anna Cały
Nicole Tay
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
IMAGEN consortium
Katarzyna Kalita
Haruhiko Bito
Christian P Müller
Gunter Schumann
Hiroyuki Okuno
Kasia Radwanska