Author(s): Lasley SM, Gilbert ME
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Abstract 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.
This article was published in Toxicol Sci
and referenced in Journal of Drug Metabolism & Toxicology