Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level.
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.
Lasley
S M
SM
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, P. O. Box 1649, Peoria, Illinois 61656, USA. sml@uic.edu
Gilbert
M E
ME
D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007854:Lead / Q000097:blood / Q000633:toxicity*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D011188:Potassium / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D007854:Lead; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011188:Potassium; D002118:Calcium