Lasley S M, Gilbert M E
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, P. O. Box 1649, Peoria, Illinois 61656, USA.
Toxicol Sci. 2002 Mar;66(1):139-47. doi: 10.1093/toxsci/66.1.139.
Previous work has suggested that the lead (Pb) exposure-induced decrease in K(+)-evoked hippocampal glutamate (GLU) release is an important factor in the elevated threshold and diminished magnitude reported for hippocampal long-term potentiation (LTP) in exposed animals. In addition, complex dose-effect relationships between Pb exposure level and LTP have been reported. This investigation was conducted to determine the effects of Pb on hippocampal GLU and GABA release as a function of exposure level. Rats were continuously exposed to 0.1, 0.2, 0.5, or 1.0% Pb in the drinking water beginning at gestational day 15-16. Hippocampal transmitter release was induced in adult males by perfusion of 150 mM K(+) in the presence of Ca(+2) (total release) through a microdialysis probe in one test session, followed by perfusion through a contralateral probe in the absence of Ca(+2) (Ca(+2)-independent release) in the second session. Chronic exposure produced decreases in total K(+)-stimulated hippocampal GLU and GABA release at exposure levels of 0.1-0.5% Pb. Maximal effects were seen in the 0.2% group (blood Pb = 40 microg/100 ml), and changes in total release could be directly traced to alterations in the Ca(+2)-dependent component. However, these effects were less evident in the 0.5% group and were no longer present in the 1.0% Pb group, thus defining U-shaped dose-effect relationships. Moreover, in the absence of Ca(+2) in the dialysis perfusate, K(+)-induced release was elevated in the 2 highest exposure groups, suggesting a Pb(+2)-induced enhancement in evoked release. This pattern of results indicates the presence of 2 actions of Pb on in vivo transmitter release: a more potent suppression of stimulated release seen at lower exposure levels (27-62 microg/100 ml) combined with Ca+2-mimetic actions to independently induce exocytosis that is exhibited at higher exposure levels (> or =62 microg/100 ml). Furthermore, significant similarities in the dose-effect relationships uncovered in measures of evoked GLU release and hippocampal LTP (M. E. Gilbert et al., 1999b, Neurotoxicology 20, 71-82) reinforce the conclusion that exposure-related changes in GLU release play a significant role in the Pb-induced effects seen in this model of synaptic plasticity.
先前的研究表明，铅（Pb）暴露导致的海马体中钾离子（K(+)）诱发的谷氨酸（GLU）释放减少，是暴露动物海马体长时程增强（LTP）阈值升高和幅度减小的一个重要因素。此外，已有报道称铅暴露水平与LTP之间存在复杂的剂量效应关系。本研究旨在确定铅对海马体GLU和γ-氨基丁酸（GABA）释放的影响，以及这种影响与暴露水平的关系。从妊娠第15 - 16天开始，大鼠持续饮用含0.1%、0.2%、0.5%或1.0%铅的水。在一个测试环节中，通过微透析探针在成年雄性大鼠海马体灌注150 mM K(+)（在存在钙离子（Ca(+2)）的情况下，即总释放）来诱导递质释放，随后在第二个环节中通过对侧探针在无Ca(+2)的情况下（即不依赖Ca(+2)的释放）进行灌注。慢性暴露在铅暴露水平为0.1 - 0.5%时，会使总K(+)刺激的海马体GLU和GABA释放减少。在0.2%组（血铅 = 40微克/100毫升）观察到最大效应，总释放的变化可直接追溯到依赖Ca(+2)的成分的改变。然而，这些效应在0.5%组中不太明显，在1.0%铅组中则不再出现，从而确定了U形剂量效应关系。此外，在透析灌注液中无Ca(+2)的情况下，最高的两个暴露组中K(+)诱导的释放增加，表明铅离子（Pb(+2)）诱导诱发释放增强。这种结果模式表明铅对体内递质释放有两种作用：在较低暴露水平（27 - 62微克/100毫升）时对刺激释放有更强的抑制作用，同时在较高暴露水平（≥62微克/100毫升）时表现出类似钙离子（Ca+2）的作用来独立诱导胞吐作用。此外，诱发的GLU释放测量结果与海马体LTP（M. E. Gilbert等人，1999b，《神经毒理学》20，71 - 82）中发现的剂量效应关系存在显著相似性，这进一步支持了以下结论：在这个突触可塑性模型中，与暴露相关的GLU释放变化在铅诱导的效应中起重要作用。
