Journal
EXPERIMENTAL NEUROLOGY
Volume 216, Issue 1, Pages 132-138Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2008.11.016
Keywords
NMDA receptors; Anxiety; Locomotor activity; Aging; Alzheimer's disease; Parkinson's disease; Schizophrenia
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Funding
- FRC, URC small grants (University of Wollongong 2007, Australia)
- Australia National Health and Medical Research Council Grant (NHMRC) [514640]
- Ramaciotti Foundations Biomedical Research Award
- Schizophrenia Research Institute
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Statins are widely being used for the treatment of a variety of conditions beyond their original indication for lowering cholesterol. We have previously reported that simvastatin affected the dopaminergic system in the rat brain. This study aims to investigate locomotor and anxiety effects along with the regional changes of N-methyl-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 high dose simvastatin (10 mg/kg/day). Distributions and alterations of NIVIDA receptors in the post-mortem rat brain were detected by [H-3] MK-801 binding autoradiography. Simvastatin increased [H-3] MK-801 binding, predominantly in the prefrontal cortex (20%, p=0.003), primary motor cortex (20%, p<0.001), cingulate cortex (28%, p<0.001), hippocampus (41%, p<0.001), caudate putamen (30%, p=0.029), nucleus accumbens (27%, p=0.035) and amygdala (45%, p<0.001) compared to controls. Significant positive correlations were identified between hyperlocomotive as well as anxiolytic-like activities and the upregulation of NIVIDA receptors in different brain regions. Our results also provide strong evidence that chronic high dose simvastatin administration is to exhibit NMDA antagonist-like effects, which would partially explain the anxiolytic and hyperlocomotor activities. These findings contribute to a better understanding of the critical roles of simvastatin in modulating psycho-neurodegenerative disorders, via NMDA receptors. (C) 2008 Elsevier Inc. All rights reserved.
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