Exercise-driven modulation of glutamatergic signaling: mechanisms and clinical implications

Exercise is increasingly recognized as a non-pharmacological intervention capable of modulating glutamatergic signaling, but most mechanistic evidence derives from animal models and human data remain scarce. Given its established role in substance use recovery, relapse prevention, and affective stabilization, exercise may act as a regulator of glutamate homeostasis in both healthy and diseased states. In this review, we synthesize findings from 57 studies published between 1998 and 2024, selected from an initial pool of 423 articles based on methodological rigor and relevance. We examine four key domains: (1) exercise-induced changes in glutamate signaling; (2) regulation of NMDA and AMPA receptor expression, phosphorylation, and trafficking; (3) modulation of glutamate-linked pathways; and (4) the impact of exercise type, intensity, and duration on glutamatergic function. Mechanistic work shows that exercise enhances NMDA and AMPA receptor phosphorylation, increases astrocytic glutamate clearance, and normalizes dysregulated signaling in models of addiction, depression, and neurodegeneration. Translational evidence from human studies reveals acute increases in cortical glutamate following vigorous exercise, supporting relevance across species. These effects are context-dependent, varying by intensity, modality, sex, and brain region, with aerobic exercise typically conferring resilience while exhaustive paradigms risk excitotoxicity. Clinical vignettes illustrate potential applications in addiction and perioperative pain management. While these findings are promising, the literature is biased toward male rodents, with limited sex-balanced or large-scale human trials. Future work should incorporate biomarker strategies, stratify by sex, genetics, and comorbidities, and expand beyond aerobic modalities to define when and for whom exercise most effectively modulates glutamatergic signaling.