Inhibition of nitric oxide synthesis impairs rapid tolerance to ethanol

To examine whether nitric oxide was involved in the development of rapid tolerance to the motor-incoordinating effects of ethanol (tilt-plane test), three experiments were undertaken in a rapid tolerance paradigm in rats. The first experiment tested the effect of the nitric oxide synthase inhibitor, L-nitro-arginine, on the acquisition of ethanol tolerance. The second compared the effects of L-nitro-arginine with those of its inactive isomer, D-nitro-arginine. The third examined whether overload with the substrate L-arginine would prevent the action of L-nitro-arginine on rapid tolerance. The results demonstrated that L-nitro-arginine prevented the development of rapid tolerance, while D-nitro-arginine was ineffective. An excess of the substrate L-arginine reversed the inhibitory action of L-nitro-arginine on tolerance development. These data suggest that nitric oxide may play a role in the development of tolerance to ethanol. The role of nitric oxide in ethanol tolerance may be similar to its role in memory and learning, involving facilitation of transmission in certain NMDA synapses.