Alcohol addiction involves dysregulation of the glutamatergic system. Here, we tested the role of Arc, one of the key regulators of the glutamatergic transmission, in the regulation of alcohol addiction. We observed that Arc KO mice drink as much alcohol as wild-type (WT) animals, but they are more persistent in alcohol seeking during alcohol withdrawal and relapse induced by alcohol-associated cues. Furthermore, we found that Arc protein is upregulated at the synapses of Basolateral (BLA) and Central Amygdala (CeA) (but not DG or CA1 of the hippocampus) in WT mice after withdrawal from long-term alcohol training. To test the function of Arc in the amygdala, we developed and tested gRNAs for Arc knockdown with CrispR/Cas9 system. The most efficient gRNA was introduced on AAV vector together with CrispR/Cas9 into CeA and mice were trained to drink alcohol or sucrose. The mice with local indel mutation of arc gene were more persistent in alcohol seeking during cue-induced relapse, had decreased levels of Arc protein in CeA, and increased levels of AMPA receptor subunit GluR2, as compared to the control animals. Local mutation of arc did not affect sucrose seeking and consumption. In conclusion, our data show the novelrole of Arc protein in CeA, as a specific regulator of alcohol seeking during relapse induced by alcohol‑associated cues.