Green K L, Grant K A
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA.
Drug Alcohol Depend. 1998 Oct 1;52(2):149-59. doi: 10.1016/s0376-8716(98)00086-6.
The present study used a drug discrimination paradigm to characterize the contribution of separate receptor systems to the stimulus effects of different training doses of ethanol. In a two-lever drug discrimination paradigm two groups of adult male Long-Evans rats (n = 8 per group) were trained to discriminate either 1.0 g/kg ethanol from water or 2.0 g/kg ethanol from water, administered intragastrically (i.g.), 30 min prior to the start of daily sessions in which responding was maintained under a fixed ratio 20 schedule of food presentation. Following training, cumulative dosing substitution tests were conducted with the GABAA positive modulator pentobarbital (1-17 mg/kg, i.p.), the uncompetitive NMDA antagonist dizocilpine (0.01-0.3 mg/kg, i.p.) and the 5-HT1B/2C agonist m-trifluoromethylphenylpiperazine (TFMPP 0.17-1.7 mg/kg, i.p.). Next, the rats initially trained at 1.0 g/kg ethanol were retrained to discriminate 2.0 g/kg ethanol from water, and the rats initially trained at 1.0 g/kg were retrained to discriminate 2.0 g/kg ethanol from water. Both groups were then re-tested with the same ligands. Regardless of training history, animals currently discriminating 1.0 g/kg were more sensitive to the ethanol-like effects of TFMPP and pentobarbital compared to rats discriminating 2.0 g/kg ethanol. However, no difference in sensitivity to the ethanol-like effects of dizocilpine based on ethanol training dose was detected. These results support the view that ethanol is a heterogeneous discriminative stimulus comprised of GABAA, NMDA and 5-HT1B/2C receptor-mediated activity. Furthermore, changes in sensitivity to GABAA and 5-HT ligands as a function of training dose could be indicative of overshadowing by other components of ethanol's heterogeneous cue. Finally, it appears that the current profile of ethanol's heterogeneous stimulus effects, rather than an interaction with ethanol training history, determines the substitution pattern of specific receptor ligands.
本研究采用药物辨别范式来描述不同受体系统对不同训练剂量乙醇刺激效应的贡献。在双杠杆药物辨别范式中，两组成年雄性Long-Evans大鼠（每组n = 8）被训练以辨别1.0 g/kg乙醇与水，或2.0 g/kg乙醇与水，通过灌胃（i.g.）给药，在每日实验开始前30分钟给药，实验中反应通过固定比例20的食物呈现时间表来维持。训练后，用GABAA阳性调节剂戊巴比妥（1 - 17 mg/kg，腹腔注射）、非竞争性NMDA拮抗剂地佐环平（0.01 - 0.3 mg/kg，腹腔注射）和5-HT1B/2C激动剂间三氟甲基苯基哌嗪（TFMPP 0.17 - 1.7 mg/kg，腹腔注射）进行累积剂量替代试验。接下来，最初在1.0 g/kg乙醇训练的大鼠重新训练以辨别2.0 g/kg乙醇与水，最初在2.0 g/kg乙醇训练的大鼠重新训练以辨别1.0 g/kg乙醇与水。然后两组大鼠都用相同的配体重新测试。无论训练历史如何，与辨别2.0 g/kg乙醇的大鼠相比，当前辨别1.0 g/kg乙醇的动物对TFMPP和戊巴比妥的类乙醇效应更敏感。然而，未检测到基于乙醇训练剂量的地佐环平类乙醇效应敏感性差异。这些结果支持了乙醇是一种由GABAA、NMDA和5-HT1B/2C受体介导的活性组成的异质性辨别刺激的观点。此外，作为训练剂量函数的对GABAA和5-HT配体敏感性的变化可能表明被乙醇异质性线索的其他成分所掩盖。最后，似乎乙醇当前的异质性刺激效应概况，而非与乙醇训练历史的相互作用，决定了特定受体配体的替代模式。
