Environmental context outweighs early methamphetamine exposure in shaping behavioral and glutamatergic outcomes in rats.

Early-life exposure to methamphetamine (MA) induces long-lasting neuroadaptive changes, particularly within glutamatergic pathways, which may contribute to behavioral and cognitive impairments. The present study investigated the interaction between early postnatal MA exposure and environmental conditions on behavioral outcomes and glutamate levels in adolescent rats. Rat pups were administered MA (5 mg/kg) or saline during postnatal days (PD) 1-12, either directly or indirectly via lactating dams. Animals were subsequently reared under different pre-weaning (standard vs. enriched environment) and post-weaning (single vs. group housing) conditions. Behavioral performance was assessed using habituation, object recognition/location, and Morris water maze tasks, while glutamate levels in the striatum and hippocampus were quantified using ELISA. Direct MA exposure induced moderate alterations in locomotor activity and spatial learning, whereas indirect exposure produced only minimal effects. In contrast, environmental conditions exerted pronounced influences on both behavior and glutamate levels. Environmental enrichment and post-weaning housing affected exploratory behavior and performance in cognitive tasks, although the direction and magnitude of these effects varied across behavioral paradigms and experimental conditions. Environmental conditions were also associated with region-specific alterations in glutamate levels, including increased striatal and decreased hippocampal glutamate under enriched pre-weaning conditions. As only male offspring were included, these findings cannot be generalized to females, and comparable effects in females cannot be assumed without direct experimental evidence. Overall, environmental factors exerted a stronger influence on behavioral and glutamatergic outcomes than early MA exposure, but their behavioral effects were task- and context-dependent rather than uniformly beneficial. These findings highlight the importance of environmental conditions in shaping neurobehavioral and glutamatergic outcomes following early-life psychostimulant exposure.