ENVIRONMENTAL ENRICHMENT COMPONENTS DIFFERENTIALLY INFLUENCE AMPHETAMINE-INDUCED BEHAVIORAL SENSITIZATION

Environmental enrichment (EE) comprises sensory, physical, social, and cognitive stimulation that can modulate neural circuits, yet it remains unclear which EE component most effectively regulates amphetamine (AMPH)-induced behavioral sensitization. Here, mice were housed under standard housing (SH), standard EE (STEE), physical EE (PEE), cognitive EE (CEE), or social EE (SEE), and assigned to saline or AMPH treatment. Animals received daily intraperitoneal injections of AMPH (1 mg/kg) or saline for 7 days, followed by a 0.5 mg/kg AMPH or saline challenge prior to behavioral testing. c-Fos immunohistochemistry was then performed in selected brain regions. AMPH produced robust locomotor sensitization, whereas anxiety-like behavior was not clearly elevated despite pronounced hyperactivity. Among EE conditions, STEE most effectively attenuated AMPH-induced sensitization compared with PEE, CEE, or SEE. AMPH increased c-Fos expression in the medial prefrontal cortex (Cg1, PrL, IL), nucleus accumbens, basolateral amygdala, ventral tegmental area, caudate–putamen, and hippocampus (CA1, CA3, dentate gyrus). STEE-related reductions in neural activation were particularly evident in the Cg1, IL, nucleus accumbens, basolateral amygdala, ventral tegmental area, caudate–putamen, CA3, and dentate gyrus. These findings indicate that comprehensive EE, rather than isolated EE components, is required to mitigate AMPH-induced behavioral and neural sensitization, highlighting the therapeutic potential of multimodal, non-pharmacological interventions in regulating drug-evoked plasticity.