The Effects of Subchronic Methamphetamine Administration on the NLRP3 Inflammasome, Memory Function, and Hippocampal Morphology

Background: While it is established that addictive doses of methamphetamine correlate with inflammation-mediated neurotoxic pathways, the extent of toxicity resulting from subchronic administration at lower doses remains uncertain.Objectives: This study aimed to investigate the subtle effects of daily subchronic methamphetamine (MA) administration on neuroinflammatory processes, cognitive dimensions, gene expression, and hippocampal morphology. Methods: The experimental study employed a longitudinal design with three groups (G1B, G2B, G3B) receiving methamphetamine (5 mg/kg, intraperitoneally, once daily) for 1, 2, or 3 weeks, respectively. Corresponding control groups (G1A, G2A, G3A) received 0.2 mL of normal saline. Spatial learning, novel object recognition, and passive avoidance tests were conducted to assess spatial, recognition, and fear avoidance memories. Hippocampal morphology was evaluated using Nissl staining, and the expressions of NLRP3, ASC, and caspase-1 genes were measured as markers of neuroinflammation. Results: Statistical analyses, including one-way and two-way ANOVA, showed that subchronic low-dose administration of MA led to significant activation of the inflammasome (NLRP3, ASC, and caspase-1), which may have resulted in pyramidal cell death in the hippocampus. The hippocampal structure in the CA1 region was completely disrupted. Spatial memory and passive avoidance learning were impaired in the MA groups, while recognition memory remained unaffected. Conclusions: The findings suggest that prolonged administration of 5 mg/kg of methamphetamine may be associated with significant inflammasome activation, pyramidal cell death, and mild cognitive decline. Contrary to previous evidence, even lower doses of methamphetamine taken over an extended period could be neurotoxic.