Methylone regulates fear memory and amygdala activity: A potential treatment for posttraumatic stress disorder?

Methylone (3,4-methylenedioxy-N-methylcathinone) is a rapid-acting entactogen that has demonstrated significant benefits for patients with post-traumatic stress disorder (PTSD) and exhibits good tolerability in phase 1 clinical trials. Despite these promising results, its preclinical effects on fear memory regulation and the underlying mechanisms remain largely unexplored. This study aims to investigate the impact of methylone on auditory fear extinction and its influence on neuronal and synaptic activity in the basolateral amygdala (BLA). Using C57BL/6 mice, we employed an auditory fear conditioning paradigm along with immunofluorescent staining, extracellular electrophysiological recording, and chemogenetic techniques. The results revealed that administering methylone at a dosage of 10 mg/kg, in conjunction with extinction trials, significantly decreased the retrieval of both recent and remote fear memories. Additionally, methylone effectively inhibited the renewal of remote fear memories and blocked spontaneous recovery. It also reduced fear generalization to both context and tone. At the cellular level, methylone increased c-fos expression in the BLA and induced sustained elevations in long-term potentiation and long-term depression at the synaptic level. Furthermore, intra-BLA microinfusion of methylone directly enhanced the extinction memory. Chemogenetic activation of the BLA mimicked the effects of methylone, whereas chemogenetic inhibition blocked them. These findings suggest that methylone modulates fear memories through its action on the BLA. This preclinical study offers a knowledge base and critical insights into the potential future application of methylone for PTSD treatment.