MDMA ENHANCES RECONSOLIDATION-BASED INTERVENTIONS TO REDUCE ALCOHOL RELAPSE

Alcohol use disorder (AUD) is a chronic, relapsing condition, with nearly 70% of individuals relapsing within one year of treatment. Relapse is often triggered by environmental cues linked to alcohol’s reinforcing effects. Disrupting these cue-alcohol associative memories offers a promising strategy for relapse prevention. The memory reconsolidation process, in which retrieved memories enter a labile state before restabilizing, provides a critical window for intervention. Psychedelic drugs such as 3,4-methylenedioxymethamphetamine (MDMA) have been suggested to enhance cognitive flexibility and memory updating during reconsolidation, offering a novel approach to memory targeting. Here, we tested MDMA’s ability to disrupt alcohol-related memory reconsolidation and reduce relapse in rats, both alone and in combination with behavioral intervention, while also examining neurobiological markers of post-retrieval effects. MDMA reduced relapse to alcohol in a two-bottle choice paradigm, but only when administered during the reconsolidation window. Gene expression analyses identified fibroblast growth factor‑2 (Fgf2), previously linked to alcohol drinking, as a correlate of post-retrieval MDMA’s behavioral effects. In a pharmaco-behavioral approach, rats underwent a post-retrieval punishment procedure with MDMA or vehicle administration to assess MDMA’s potential to enhance the efficacy of the behavioral intervention. MDMA enhanced the relapse-suppressing effect of post-retrieval punishment when administered after training, but only within the reconsolidation window. Together, these findings demonstrate that MDMA can augment behavioral relapse-prevention strategies by enhancing memory updating during reconsolidation. This work supports further exploration of MDMA-assisted memory reconsolidation targeting as a novel therapeutic approach for relapse prevention in addiction and other memory-based disorders.
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