Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats

The effects of N-G-nitro arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), nitric oxide synthase inhibitors, and L-arginine, a nitric oxide precursor, on ethanol withdrawal signs were investigated in rats. Ethanol (7.2% v/v) was given to rats by a liquid diet for 16 days. L-NAME (30 and 60 mg/kg), 7-NI (40 and 80 mg/kg), L-arginine (100 mg/kg), a combination of L-arginine (100 mg/kg) and 7-NI (40 mg/kg), and saline or vehicle were injected to rats intraperitoneally 30 min before ethanol withdrawal. A second series of injections was given at 6 hour after the first one, and subjects were then tested for audiogenic seizures. 7-NI (40 mg/kg), vehicle and saline were also administered to naive rats. 7-NI (40 mg/kg) did not produce any significant change in locomotor activity in naive rats. Both L-NAME and 7-NI significantly inhibited locomotor hyperactivity from the 2nd to the 6th hour of the withdrawal period. They also reduced the total ethanol withdrawal score from the 30th min to the 6th hour, and they significantly decreased audiogenic seizures. Neither drug increased locomotor activity nor total ethanol withdrawal score, which were increased significantly by L-arginine (100 mg/kg); however, L-arginine (100 mg/kg) prevented the inhibitory effects of 7-NI (40 mg/kg) on increased locomotor activity, total ethanol withdrawal score, and audiogenic seizure. Our results suggest that nitric oxide synthase inhibition by L-NAME and 7-NI alleviates the signs of ethanol withdrawal. The data also support the hypothesis that nitric oxide may take part in the neuroadaptation that develops during chronic ethanol ingestion in rats.