Adenosine A2A Receptor Contributes to Bidirectional Remodeling of Microglial Inflammatory Responses During Methamphetamine Exposure

To investigate the role of the adenosine A2A receptor (A2AR) in methamphetamine (MA)-induced microglia-mediated neuroinflammation and to explore the potential signaling mechanism, postmortem human striatal tissue from MA users, a male C57BL/6 mouse model of MA exposure, and the human microglial cell line HMC3 were examined by Western blotting, immunofluorescence, and related assays. Across all three experimental systems, MA exposure significantly upregulated A2AR expression together with alterations in downstream PKA and PKC signaling. These signaling changes were accompanied by parallel upregulation of pro-inflammatory mediators (iNOS, IL-1β, and IL-18) and of anti-inflammatory and repair-associated factors (Arg-1 and IL-10), suggesting that MA did not trigger a simple unidirectional inflammatory program but instead induced multidimensional phenotypic remodeling of microglia that varied with exposure time and dose. Intervention with the selective A2AR antagonist SCH58261 showed that pharmacological inhibition of A2AR markedly attenuated MA-induced alterations in PKA/PKC signaling and suppressed the accompanying shifts in inflammatory mediator expression, thereby mitigating the neuroinflammatory response. These results suggest that A2AR is involved in the modulation of MA-induced microglial inflammatory responses and may contribute to the mixed inflammatory state characterized by simultaneous changes in pro-inflammatory and anti-inflammatory markers, possibly associated with PKA/PKC signaling. This study expands current understanding of the inflammatory basis of MA-related neurotoxicity and suggests A2AR as a potential target for therapeutic intervention in MA abuse.