INACTIVATION OF CEREBELLAR NITRIC OXIDE SYNTHASE BY ETHANOL IN VITRO

The N-methyl-D-aspartate receptor/nitric oxide synthase (NOS)/guanylatecyclase pathway, which plays a crucial role in synaptic plasticityin the brain, is modulated by ethanol. We studied the effectof ethanol in vitro on NOS in rat cerebellum and showed thatethanol (25–200 mM) inactivated NOS in a dose-dependentmanner. This inactivation was prevented by the biopterin cofactortetrahydrobiopterin (BH⁴) as well as by L-arginine, a NOS substrate,but not by NADPH. These results suggest that ethanol reducesNOS activity by modulating the conformation of the enzyme andthereby its stability, probably by interacting with the bindingsites of BH⁴ and/or of L-arginine. Our data also suggest thatinactivation of NOS may contribute to the decrease in the cGMPlevel, and thus may play a role in the pharmacological actionsof ethanol in vivo.