Cory-Slechta D A
Department of Neurobiology and Anatomy, University of Rochester, School of Medicine and Dentistry, NY 14642, USA.
Neurotoxicology. 1997;18(1):209-20.
Postweaning Pb exposure has been associated with subsensitivity to the stimulus properties of the non-competitive NMDA receptor complex antagonist MK-801 (Cory-Slechta, 1995a). This study sought to determine whether Pb exposures occurring postnatally, i.e., during the primary period of development of many NMDA receptor subunits, would alter the nature of these glutamatergic system changes. Rat pups were exposed to Pb from 0-21 days of age via lactating dams consuming solutions of 0, 100 or 350 ppm Pb acetate. Beginning at 9 mos of age, rats were trained to discriminate 0.05 mg/kg MK-801 from saline using standard operant drug discrimination procedures. Following acquisition of the discrimination, various doses of MK-801, the non-competitive antagonist phencyclidine (PCP), the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP) and the agonist N-methyl-D-aspartate (NMDA) were substituted for 0.05 mg/kg MK-801 and percent MK-801 lever responding to each determined. Subsequently, a drug washout period was imposed, after which MK-801 dose-effect curves were re-established. Increasing doses of MK-801 and PCP produced dose-dependent increases in MK-801 lever responding resulting in full substitution, whereas CPP and NMDA evoked primarily saline-appropriate responding. Pb exposure was associated with enhanced MK-801 sensitivity during the pre-washout phase, but attenuated sensitivity following MK-801 washout. In both cases, however these effects were of relatively modest magnitude. No systematic Pb-related changes in response to PCP, CPP or NMDA were observed. These data raise the possibility, particularly when considered in relation to studies based on other Pb exposure protocols, that NMDA receptor changes may depend upon ongoing or extant Pb exposures, or that postnatal exposure effects on this system may be largely reversible. In addition, the differential nature of the effects seen with postnatal vs postweaning exposure (Cory-Slechta, 1995a) underscores the significance of the developmental period of exposure to Pb effects on the NMDA receptor complex.
断奶后铅暴露与对非竞争性N-甲基-D-天冬氨酸（NMDA）受体复合物拮抗剂MK-801的刺激特性敏感性降低有关（科里-斯莱赫塔，1995年a）。本研究旨在确定出生后即许多NMDA受体亚基发育的主要时期发生的铅暴露是否会改变这些谷氨酸能系统变化的性质。通过让哺乳期母鼠饮用含0、100或350 ppm醋酸铅溶液，使幼鼠在0至21日龄期间暴露于铅环境中。从9月龄开始，使用标准操作性药物辨别程序训练大鼠区分0.05 mg/kg MK-801和生理盐水。在获得辨别能力后，用各种剂量的MK-801、非竞争性拮抗剂苯环己哌啶（PCP）、竞争性拮抗剂3-（2-羧基哌嗪-4-基）丙基-1-膦酸酯（CPP）和激动剂N-甲基-D-天冬氨酸（NMDA）替代0.05 mg/kg MK-801，并确定对每种药物的MK-801杠杆反应百分比。随后，进行药物洗脱期，之后重新建立MK-801剂量效应曲线。剂量增加的MK-801和PCP导致MK-801杠杆反应呈剂量依赖性增加，最终完全替代，而CPP和NMDA主要引起与生理盐水相应的反应。在洗脱前阶段，铅暴露与MK-801敏感性增强有关，但在MK-801洗脱后敏感性减弱。然而，在这两种情况下，这些影响的程度相对较小。未观察到与铅相关的对PCP、CPP或NMDA反应的系统性变化。这些数据提出了一种可能性，特别是与基于其他铅暴露方案的研究相关时，即NMDA受体变化可能取决于持续或现存的铅暴露，或者出生后暴露对该系统的影响可能在很大程度上是可逆的。此外，出生后与断奶后暴露所观察到的效应的差异性质（科里-斯莱赫塔，1995年a）强调了铅暴露发育时期对NMDA受体复合物影响的重要性。
