Willetts J, Balster R L
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
J Pharmacol Exp Ther. 1989 Nov;251(2):627-33.
Competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists and other central nervous system depressants were assessed for their ability to antagonize the discriminative stimulus effects of NMDA in rats trained under a standard two-lever fixed ratio schedule of food reinforcement. The competitive NMDA antagonists, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate and NPC 12626 [2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate], dose-dependently antagonized NMDA-lever selection at doses that did not affect rates of responding. Conversely, the noncompetitive NMDA antagonists, phencyclidine, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] and (+)-N-allylnormetazocine, as well as pentobarbital and diazepa, all reduced response rates dose-dependently without antagonism of NMDA-lever responding. In stimulus generalization tests, NPC 12626 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate at doses higher than those required to antagonize NMDA, often elicited NMDA-lever responding. The mechanisms underlying the similarities in the interoceptive stimuli produced by NMDA and its competitive antagonists remain to be determined. These results indicate that although competitive NMDA antagonists antagonize effects of NMDA without concomitant behavioral disruption, noncompetitive NMDA antagonists and central nervous system depressants are behaviorally disruptive at doses that do not antagonize NMDA. The results provide further evidence for differences in the behavioral profiles of competitive and noncompetitive NMDA antagonists.
在以标准双杠杆固定比率食物强化程序训练的大鼠中，评估了竞争性和非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂及其他中枢神经系统抑制剂拮抗NMDA辨别性刺激效应的能力。竞争性NMDA拮抗剂3-(2-羧基哌嗪-4-基)丙基-1-膦酸酯和NPC 12626 [2-氨基-4,5-(1,2-环己基)-7-膦酰基庚酸]，在不影响反应率的剂量下，剂量依赖性地拮抗了NMDA杠杆选择。相反，非竞争性NMDA拮抗剂苯环利定、MK-801 [(+)-5-甲基-10,11-二氢-5H-二苯并(a,d)环庚烯-5,10-亚胺马来酸盐]和(+)-N-烯丙基去甲佐辛，以及戊巴比妥和地西泮，均剂量依赖性地降低了反应率，而未拮抗NMDA杠杆反应。在刺激泛化试验中，NPC 12626和3-(2-羧基哌嗪-4-基)丙基-1-膦酸酯在高于拮抗NMDA所需的剂量时，常常引发NMDA杠杆反应。NMDA及其竞争性拮抗剂产生的内感受性刺激相似性的潜在机制仍有待确定。这些结果表明，尽管竞争性NMDA拮抗剂拮抗NMDA的效应而不伴有行为干扰，但非竞争性NMDA拮抗剂和中枢神经系统抑制剂在不拮抗NMDA的剂量下会造成行为干扰。这些结果为竞争性和非竞争性NMDA拮抗剂行为特征的差异提供了进一步的证据。
