High doses of simvastatin upregulate dopamine D1 and D2 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 mu 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 mu M). 6 D-2 receptor activation by quinpirole (5 mu 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.