Toxicological Sciences 66, 139-147 (2002)
Copyright © 2002 by the Society of Toxicology
NEUROTOXICOLOGY |
Rat Hippocampal Glutamate and GABA Release Exhibit Biphasic Effects as a Function of Chronic Lead Exposure Level
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* Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, P. O. Box 1649, Peoria, Illinois 61656;
Neurotoxicology Division, U. S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and
Department of Psychology, University of North Carolina, Chapel Hill, North Carolina 27599
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 µg/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 vivotransmitter release: a more potent suppression of stimulated release seen at lower exposure levels (27–62 µg/100 ml) combined with Ca+2-mimetic actions to independently induce exocytosis that is exhibited at higher exposure levels (
62 µg/100 ml). Furthermore, significant similarities in the dose-effect relationships uncovered in measures of evoked GLU release and hippocampal LTP (M. E. Gilbertet al., 1999b,Neurotoxicology20, 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.
Key Words: lead; glutamate; GABA; hippocampus; biphasic; long-term potentiation; microdialysis; calcium.
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