High dose of simvastatin induces hyperlocomotive and anxiolytic-like activities: The association with the up-regulation of NMDA receptor binding in the rat brain.
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 NMDA receptors in the post-mortem rat brain were detected by [(3)H] MK-801 binding autoradiography. Simvastatin increased [(3)H] 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 NMDA 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.
Wang
Qing
Q
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, NSW, Australia. denniswq@yahoo.com
Zengin
Ayse
A
Deng
Chao
C
Li
Yun
Y
Newell
Kelly A
KA
Yang
Guo-Yuan
GY
Lu
Ying
Y
Wilder-Smith
Einar P
EP
Zhao
Heng
H
Huang
Xu-Feng
XF
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006948:Hyperkinesis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D014151:Anti-Anxiety Agents; D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D019821:Simvastatin