Arc controls alcohol cue relapse by a central amygdala mechanism

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 identi ed 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.

Is DNA methylation in the brain a mechanism of alcohol use disorder?

“…Interestingly, knockdown of Hif3a expression in the central nucleus of amygdala (CeA) attenuated acute ethanol-induced anxiolysis. Decreased activity regulated cytoskeleton associated protein ( Arc ) gene methylation and increased mRNA expression was also found in the amygdala of mice drinking alcohol ( Pagano et al, 2022 ). Arc gene methylation levels correlated with alcohol seeking during withdrawal, not alcohol consumption; while Arc mRNA levels were increased in mice diagnosed with AUD-resistant phenotype.…”

“…Most of the studies relate to alcohol consumption during free access without demonstration of the causative role of the methylation in the behavior. Up to date there are only a few observations that link DNA methylation with AUD-related behaviors beyond free access alcohol consumption, including the correlation of DNA methylation with compulsive alcohol drinking ( Barbier et al, 2015 ), anxiolysis ( Krishnan et al, 2022 ) and alcohol seeking induced by alcohol-predicting cues ( Pagano et al, 2022 ).…”

“…The role of DNA methylation in the regulation of AUD-related behaviors beyond quantitative aspects of alcohol consumption, such as motivation to drink, alcohol craving, compulsive alcohol seeking and drinking or propensity for relapse, remain largely unknown, with rare exception where gene methylation was linked with compulsive alcohol use ( Barbier et al, 2015 ), anxiolysis ( Krishnan et al, 2022 ) or alcohol motivation and seeking ( Pagano et al, 2022 ). Furthermore, the effect of alcohol use on the expression of the enzymes regulating DNA demethylation (TET and Alkb) in the brain still remain mostly unknown.…”

Autophosphorylation of αCaMKII regulates alcohol consumption by controlling sedative effects of alcohol and alcohol-induced loss of excitatory synapses

“…How do the alterations of the glutamatergic synapses in CeA of the T286A +/mice contribute to AUDrelated behavior? CeA has been implicated in the regulation of multiple behaviors that contribute to AUD, including: compulsive alcohol taking [17,18], incubation of alcohol craving [19], reinstatement of alcohol seeking by the cues associated with alcohol reward [20,21], withdrawal syndrome and conditioned place aversion induced by acute drug withdrawal [22,23,48], and voluntary abstinence [24,25]. Moreover, anxiety-related alcohol consumption is likely dependent on CeL/C amygdala as its function was previously linked with anxiety, perception of nociceptive signals, punishment-resistant alcohol consumption and drug craving [18,24,[49][50][51].…”

“…Finally, we employed chemogenetic inhibition of the central nucleus of the amygdala (CeA) to study its role in AUD-related behaviors in the IntelliCages and Serial Block-Face Scanning Electron Microscopy (SBEM) [16] to study the role of T286A +/in the regulation of alcohol-induced synaptic plasticity in CeA. We focused on the amygdala as it has been implicated in the regulation of multiple behaviors that contribute to AUD, including: compulsive (despite negative consequences) alcohol consumption [17,18], incubation of alcohol craving [19], reinstatement of alcohol seeking by the cues associated with alcohol reward [20,21], withdrawal syndrome and conditioned place aversion induced by acute drug withdrawal [22,23], and voluntary abstinence [24,25].…”