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

1 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. 2 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. 3 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. 4 Simvastatin (10 mg kg −1  day −1 ) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS. 5 D 1 receptor activation by chloro‐APB (5  μ M ) 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  μ M ). 6 D 2 receptor activation by quinpirole (5  μ M ) 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. 7 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.British Journal of Pharmacology (2005) 144 , 933–939. doi: 10.1038/sj.bjp.0706106