The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine

Methamphetamine (METH) is known to induce neuroinflammation and toxicity in brain regions associated with reward, such as the nucleus accumbens, prefrontal cortex, and ventral tegmental area. While microglia—the brain's primary immune cells—are typically implicated in this response, the precise mechanism of action remains poorly understood. This study investigated whether METH activates microglia directly or whether the drug causes neuroinflammation indirectly by triggering the release of damage-associated molecular patterns (DAMPs) from neurons.

Researchers administered a neurotoxic dose of METH (10 mg/kg) to rats and measured the inflammatory response in key brain reward structures over several hours. To determine if this was a direct effect, they exposed isolated primary microglia to METH in vitro. Finally, to test the role of the DAMP high mobility group box-1 (HMGB1), they used an intracranial injection of box A, a competitive antagonist that blocks HMGB1 binding to Toll-like receptor 4 (TLR4), before administering METH.

• Neuroinflammatory Response: Acute METH treatment robustly increased the expression of pro-inflammatory markers, particularly IL-1β, across the nucleus accumbens, prefrontal cortex, and ventral tegmental area.
• Direct vs. Indirect Activation: In vitro exposure of microglia to METH failed to provoke a pro-inflammatory response; instead, high concentrations led to reduced cell viability, suggesting that METH does not directly stimulate microglia to release cytokines.
• The Role of HMGB1: METH treatment significantly increased levels of HMGB1 protein in the striatum. Crucially, pre-treatment with the HMGB1 antagonist box A effectively blocked the METH-induced increase in IL-1β, demonstrating that HMGB1 is a critical mediator in the neuroinflammatory cascade triggered by the drug.