Physical exercise is a widely accepted behavioral strategy to enhance overall health, including mental function. However, there is controversial evidence showing brain mitochondrial dysfunction, oxidative damage and decreased neurotrophin levels after high-intensity exercise, which presumably worsens cognitive performance. Here we investigated learning and memory performance dependent on different brain regions, glutathione antioxidant system, and extracellular signal-regulated protein kinase 1/2 (ERK1/2), serine/threonine protein kinase (AKT), cAMP response element binding (CREB) and dopamine- and cyclic AMP-regulated phosphoprotein (DARPP)-32 signaling in adult Swiss mice submitted to 9 weeks of high-intensity exercise. The exercise did not alter the animals' performance in the reference and working memory versions of the water maze task. On the other hand, we observed a significant impairment in the procedural memory (an implicit memory that depends on basal ganglia) accompanied by a reduced antioxidant capacity and ERK1/2 and CREB signaling in this region. In addition, we found increased striatal DARPP-32-Thr-75 phosphorylation in trained mice. These findings indicate an increased vulnerability of the striatum to high-intensity exercise associated with the disruption of implicit memory in mice and accompanied by alteration of signaling proteins involved in the plasticity of this brain structure.