Statins are widely being used for the treatment of a variety of conditions beyond their original indication forlowering cholesterol. We have previously reported that simvastatin affected the dopaminergic system in therat brain. This study aims to investigate locomotor and anxiety effects along with the regional changes of Nmethyl-D-aspartate (NMDA) receptors in the rat brain after 4-week administration of simvastatin.Hyperlocomotive and anxiolytic-like activities in the rat were observed after chronic administration of highdose simvastatin (10 mg/kg/day). Distributions and alterations of NMDA receptors in the post-mortem ratbrain were detected by [3H] MK-801 binding autoradiography. Simvastatin increased [3H] MK-801 binding,predominantly in the prefrontal cortex (20%, p=0.003), primary motor cortex (20%, pb0.001), cingulatecortex (28%, pb0.001), hippocampus (41%, pb0.001), caudate putamen (30%, p=0.029), nucleus accumbens(27%, p=0.035) and amygdala (45%, pb0.001) compared to controls. Significant positive correlations wereidentified between hyperlocomotive as well as anxiolytic-like activities and the upregulation of NMDAreceptors in different brain regions. Our results also provide strong evidence that chronic high dosesimvastatin administration is to exhibit NMDA antagonist-like effects, which would partially explain theanxiolytic and hyperlocomotor activities. These findings contribute to a better understanding of the criticalroles of simvastatin in modulating psycho-neurodegenerative disorders, via NMDA receptors.