High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase.
This study aims to investigate whether or not long-term statin treatment causes upregulation of D1 and D2 receptor gene expression with concomitant increase in endothelial nitric oxide synthase (eNOS) expression in Sprague-Dawley rats. Serum triglyceride levels were dose dependently reduced in the simvastatin-treated rats reaching statistical significance at the highest dose (49% reduction), while pravastatin caused similar effects (52%) at the same dose. Cholesterol levels remained unchanged in both groups at all doses. Simvastatin, 10 or 30 mg kg(-1) day(-1), increased D1 and D2 receptor expressions in the prefrontal cortex. Similar upregulation was observed neither with simvastatin in the striatum nor with pravastatin in both brain regions. Simvastatin (10 mg kg(-1) day(-1)) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS. D1 receptor activation by chloro-APB (5 microM) increased cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats by 88 and 285%, respectively. This effect was markedly attenuated by the selective D1 antagonist SCH-23390 (25 microM). D2 receptor activation by quinpirole (5 microM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats, while the same concentration of quinpirole completely abolished the D1 receptor-mediated increase. These results suggest that lipophilic statins can alter dopaminergic functions in the prefrontal cortex possibly via a central mechanism. The possibility of a nitric oxide mechanism involving eNOS requires further investigation.
Wang
Qing
Q
Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2, 18 Medical Drive, Singapore 117597, Singapore.
Ting
Wee Lee
WL
Yang
Hongyuan
H
Wong
Peter T-H
PT
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004334:Drug Administration Schedule; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis* / Q000235:genetics; D019821:Simvastatin / Q000008:administration & dosage*; D015854:Up-Regulation / Q000187:drug effects*
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat