High doses of simvastatin upregulate dopamine D 1 and D 2 receptor expression in the rat prefrontal cortex: Possible involvement of endothelial nitric oxide synthase

Abstract

This study aims to investigate whether or not long-term statin treatment causes upregulation of D 1 and D 2 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 D 1 and D 2 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. D 1 receptor activation by chloro-APB (5 μM) 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 D 1 antagonist SCH-23390 (25 μM). D 2 receptor activation by quinpirole (5 μM) 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 D 1 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. © 2005 Nature Publishing Group. All rights reserved.