Wang Benfu, Lv Kun, Liu Huifeng, Su Yin, Wang Hong, Wang Sicong, Bao Suhao, Zhou Wen-Hua, Lian Qing-Quan
Department of Anesthesiology, Second Affiliated Hospital and Institute of Neuroendocrinology, Wenzhou Medical University, Wenzhou.
Department of Anesthesiology, Jining First People's Hospital, Jining, Shandong Province, People's Republic of China.
Neuroreport. 2018 Mar 21;29(5):347-352. doi: 10.1097/WNR.0000000000000959.
Propofol as an agonist of GABAA receptor has a rewarding and discriminative stimulus effect. However, which subtype of the GABAA receptor is involved in the discriminative stimulus effects of propofol is still not clear. We observed the effects of an agonist or an antagonist of the subtype-selective GABAA receptor on discriminative stimulus effects of propofol. Male Sprague-Dawley rats were trained to discriminate 10 mg/kg (intraperitoneal) propofol from intralipid under a fixed-ratio 10 schedule of food reinforcement. We found that propofol produced dose-dependent substitution for propofol at 10 mg/kg, with response rate reduction only at a dose above those producing the complete substitution. CL218,872 (1-3 mg/kg, intraperitoneal), an α1 subunit-selective GABAA receptor agonist, and SL651,498 (0.3-3 mg/kg, intraperitoneal), an α2/3 GABAA receptor selective agonist, could partially substitute for the discriminative stimulus effects of propofol (40-80% propofol-appropriate responding). Meanwhile, L838,417 (0.2-0.6 mg/kg, intravenous), a α2/3/5 GABAA receptor selective agonist, could produce near 100% propofol-appropriate responding and completely substitute for propofol effects. Moreover, the administration of L655,708, the α5 GABAA receptor inverse agonist, could dose dependently attenuate the discriminative stimulus of propofol. In contrast, the α1 GABAA receptor antagonist β-CCt (1-3 mg/kg) combined with propofol (10 mg/kg) failed to block the propofol effect. The data showed that propofol produces discriminative stimulus effects in a dose-dependent manner and acts mainly on the α5 GABAA to produce the discriminative stimulus effect.
丙泊酚作为γ-氨基丁酸A型（GABAA）受体激动剂具有奖赏性和辨别性刺激效应。然而，丙泊酚的辨别性刺激效应涉及GABAA受体的哪种亚型仍不清楚。我们观察了亚型选择性GABAA受体激动剂或拮抗剂对丙泊酚辨别性刺激效应的影响。雄性Sprague-Dawley大鼠在固定比率10的食物强化程序下接受训练，以区分10毫克/千克（腹腔注射）丙泊酚和脂质乳剂。我们发现，丙泊酚在10毫克/千克时产生剂量依赖性的丙泊酚替代作用，仅在高于产生完全替代作用的剂量时反应率才降低。CL218,872（1 - 3毫克/千克，腹腔注射），一种α1亚基选择性GABAA受体激动剂，以及SL651,498（0.3 - 3毫克/千克，腹腔注射），一种α2/3 GABAA受体选择性激动剂，可部分替代丙泊酚的辨别性刺激效应（40 - 80%的丙泊酚适宜反应）。同时，L838,417（0.2 - 0.6毫克/千克，静脉注射），一种α2/3/5 GABAA受体选择性激动剂，可产生接近100%的丙泊酚适宜反应并完全替代丙泊酚效应。此外，α5 GABAA受体反向激动剂L655,708的给药可剂量依赖性地减弱丙泊酚的辨别性刺激。相比之下，α1 GABAA受体拮抗剂β-CCt（1 - 3毫克/千克）与丙泊酚（10毫克/千克）联合使用未能阻断丙泊酚效应。数据表明，丙泊酚以剂量依赖性方式产生辨别性刺激效应，主要作用于α5 GABAA受体以产生辨别性刺激效应。
