The nitric oxide synthase inhibitor L-NAME (N omega-nitro-L-arginine methyl ester) does not produce discriminative stimulus effects similar to ethanol.

N-methyl-D-aspartate (NMDA) antagonists substitute for the discriminative stimulus effects of ethanol, indicating that a component of ethanol's behavioral activity is produced via blockade of NMDA receptor/channel function. Recently, it has been reported that ethanol inhibits NMDA-stimulated nitric oxide synthase (NOS) activity in cortical neurons, thereby decreasing the formation of nitric oxide (NO) in the brain. These findings suggest that some of the behavioral effects of ethanol may be mediated by inactivation of NOS. The present study examined the role of NO formation in mediating the discriminative stimulus effects of ethanol. To address this hypothesis, an NOS inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) and an NMDA competitive antagonist, (D)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (CPPene), were administered to two groups of rats trained to discriminate 1.5 g/kg of ethanol (n = 6) or 2.0 g/kg (n = 7) of ethanol from water. After training, dose ranges of CPPene (3 to 17 mg/kg, ip) and L-NAME (100 to 780 mg/kg, ip) were tested for ethanol-like effects. L-NAME was also tested under a range of pretreatment times (20, 60, 90, and 120 min). An additional group of rats trained to discriminate 2.0 g/kg (n = 7) of ethanol from water was also tested with CPPene (10 mg/kg, ip) and L-NAME (100 and 300 mg/kg, ip) to verify data gathered from the original 2.0 g/kg of ethanol group tested with L-NAME after a 20-minute pretreatment. Although overall, 17 of 20 animals trained to discriminate ethanol from water exhibited complete substitution of CPPene for ethanol, L-NAME, without affecting response rates, did not consistently substitute for either 1.5 g/kg or 2.0 g/kg of ethanol. These results indicate that inhibition of NO formation is less effective than direct NMDA receptor antagonism in producing ethanol-like discriminative stimulus effects.