Identification of SAA1 in extracellular vesicles contribute to methamphetamine withdrawal

Anxiety and depression-like symptoms are highly prevalent among methamphetamine (MA) users, particularly during the acute withdrawal (AW) phase, which plays a crucial role in the high relapse rates observed in this population. Despite their clinical importance, the mechanisms driving these withdrawal symptoms remain largely unclear. In this study, we focused on the plasma extracellular vesicles (EVs) in the MA users during the acute withdrawal (MA-AW EVs). Our findings demonstrate that the transplantation of MA-AW EVs induces anxiety and depression-like behaviors in mice, suggesting a direct link between EVs and affective withdrawal symptoms. In vivo and in vitro analyses further revealed that transplantation of MA-AW EVs induces alterations in neuronal and synaptic morphology, with withdrawal-related behaviors manifesting in a microglia-dependent manner. Proteomic profiling revealed that the EVs contained serum amyloid A-1 (SAA1) and serum amyloid A-2 (SAA2) proteins closely linked to the duration of MA withdrawal. These proteins were notably upregulated during the AW phase and declined rapidly during the protracted withdrawal (PW) stage. Subsequent experiments further validated the critical role of SAA1 in mediating anxiety and depression-like behaviors, neurotoxicity, synaptic plasticity and microgliosis. Our findings underscore the pivotal role of EVs in the MA process and suggest a close relationship between SAA1 protein and withdrawal symptoms, which may potentially serve as a novel target for MA addiction intervention.