Green K L, Gatto G J, Grant K A
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Winston-Salem, NC 27157-1083, USA.
Alcohol Clin Exp Res. 1997 May;21(3):483-8.
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.
N-甲基-D-天冬氨酸（NMDA）拮抗剂可替代乙醇的辨别性刺激效应，这表明乙醇行为活性的一个组成部分是通过阻断NMDA受体/通道功能产生的。最近，有报道称乙醇可抑制皮质神经元中NMDA刺激的一氧化氮合酶（NOS）活性，从而减少大脑中一氧化氮（NO）的生成。这些发现表明，乙醇的某些行为效应可能是由NOS失活介导的。本研究考察了NO生成在介导乙醇辨别性刺激效应中的作用。为验证这一假设，将一种NOS抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME）和一种NMDA竞争性拮抗剂（D）-4-（3-膦酰基-2-烯丙基）哌嗪-2-羧酸（CPPene）给予两组经训练能从水中辨别出1.5 g/kg乙醇（n = 6）或2.0 g/kg乙醇（n = 7）的大鼠。训练后，测试了CPPene（3至17 mg/kg，腹腔注射）和L-NAME（100至780 mg/kg，腹腔注射）的剂量范围对乙醇样效应的影响。还在一系列预处理时间（20、60、90和120分钟）下测试了L-NAME。另一组经训练能从水中辨别出2.0 g/kg乙醇（n = 7）的大鼠也用CPPene（10 mg/kg，腹腔注射）和L-NAME（100和300 mg/kg，腹腔注射）进行了测试，以验证在20分钟预处理后用L-NAME测试的原始2.0 g/kg乙醇组收集的数据。尽管总体而言，20只经训练能从水中辨别出乙醇的动物中有17只表现出CPPene完全替代乙醇，但L-NAME在不影响反应率的情况下，并未始终如一地替代1.5 g/kg或2.0 g/kg的乙醇。这些结果表明，在产生乙醇样辨别性刺激效应方面，抑制NO生成的效果不如直接拮抗NMDA受体。
