Grant K A, Colombo G, Grant J, Rogawski M A
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1083, USA.
Neuropharmacology. 1996;35(12):1709-19. doi: 10.1016/s0028-3908(96)00147-5.
The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (+/-)-5-aminocarbonyl-10,11-dihydro -5H-dibenzo-[a,d]cyclohepten-5,10-imine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low-affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.
在一个双杠杆操作性实验程序中，对经过训练能够区分地佐环平（0.17毫克/千克，腹腔注射）和生理盐水的大鼠，研究了多种通道阻断（非竞争性）N-甲基-D-天冬氨酸（NMDA）受体拮抗剂类地佐环平样辨别刺激效应。解离麻醉型NMDA拮抗剂地佐环平（半数有效剂量[ED50]为0.05毫克/千克）、苯环利定（ED50为3.4毫克/千克）和氯胺酮（ED50为14毫克/千克）表现出完全替代，且未导致反应率显著下降，而右吗拉胺（ED50为4.3毫克/千克）也产生了完全替代，同时反应率下降了35%。同样，低亲和力拮抗剂美金刚在显著降低（68%）反应率的剂量下导致完全替代（ED50为9.7毫克/千克）。所有其他低亲和力拮抗剂在显著降低平均反应率的剂量下，对 地佐环平的辨别刺激效应要么产生部分替代，要么不产生替代。这些拮抗剂包括（括号内为ED50值）瑞马西胺（29毫克/千克）、瑞马西胺代谢物1,2 - 二苯基 - 2 - 丙胺（ARL 12495）（14毫克/千克）、苯环环戊胺（25毫克/千克）、右美沙芬（46毫克/千克）、（±）-5 - 氨基羰基 - 10,11 - 二氢 - 5H - 二苯并[a,d]环庚烯 - 5,10 - 亚胺（ADCI；无替代）和左吗拉胺（无替代）。我们得出结论，低亲和力非竞争性NMDA拮抗剂具有与解离麻醉型非竞争性NMDA拮抗剂不同的辨别刺激特性。亲和力最低的拮抗剂对地佐环平几乎没有替代作用，而相对效力更强的低亲和力拮抗剂（如美金刚）表现出更大的替代作用，但只有在降低反应率的剂量下才能实现完全替代。
