The general objective is to determine the mechanisms mediating the acute effects of toxic heavy metals on synaptic transmission. More specifically, the in vitro effects of inorganic Pb and Hq as well as ethyl and methyl compounds of Pb, Hg and Sn on depolarization-evoked and spontaneous neurotransmitter release will be examined in a coordinated research program employing both the frog skeletal neuromuscular junction (electrophysiology) and three different types of rat brain synaptosomes (neurochemistry). Recent studies have shown that the effects of inorganic Pb, Cd and Hg on rat brain GABAergic, DAergic and cholinergic synapses are remarkably similar to their effects previously demonstrated in the frog -- even though the effects of each of these metals are distinctly different one from another. Therefore, our working hypothesis is that many of the basic mechanisms of action of a narticular toxic metal are similar or identical for a wide variety of chemical synapses both central and peripheral. Thus, we propose that the electrophysiological and neurochemical test systems, each with distinctive powers and limitations, can be used to considerable advantage to further document the effects of heavy metals and to explore their mechanisms of action. The first specific objective is to complete the task of determining the basic effects of the toxic metals on neurotransmitter release for the purpose of establishing similarities and differences between (a) the effects of a particular heavy metal on different transmitter systems (b) the effects of different heavy metals on a particular neurotransmitter system (c) inorganic and organic forms of metal (d) ethyl and methyl compounds of a metal. These data should then provide a strong foundation for approaching the second major objective, that of clarifying the cellular mechanisms of action of Pb, Hg and Sn. Particular attention will be given to efforts aimed at discriminating between mechanisms involving (a) effects on transmembrane Cafluxes, (b) indirect effects possibly resulting from enzyme inhibition and (c) more or less direct effects on neurotransmitter release. These experiments are expected not only to significantly advance our understanding of the acute neurotoxic effects of organic and inorganic heavy metals but also to provide a much more substantial foundation than would otherwise be possible upon which to plan further research devoted to their chronic neurotoxicity.
| Minnema, D J; Cooper, G P; Schamer, M M (1991) Differential effects of triethyllead on synaptosomal [3H]dopamine vs. [3H]acetylcholine and [3H]gamma-aminobutyric acid release. Neurotoxicol Teratol 13:257-65 |
| Hare, M F; Rezazadeh, S M; Cooper, G P et al. (1990) Effects of inorganic mercury on [3H]dopamine release and calcium homeostasis in rat striatal synaptosomes. Toxicol Appl Pharmacol 102:316-30 |
| Hare, M F; Minnema, D J; Cooper, G P et al. (1989) Effects of mercuric chloride on [3H]dopamine release from rat brain striatal synaptosomes. Toxicol Appl Pharmacol 99:266-75 |
| Minnema, D J; Michaelson, I A; Cooper, G P (1988) Calcium efflux and neurotransmitter release from rat hippocampal synaptosomes exposed to lead. Toxicol Appl Pharmacol 92:351-7 |
