Alkylmetals were studied for their potential to produce selective neurobehavioral and neurochemical alterations in limbic forebrain function. Short-term repeated or acute exposure to triethyl lead (TEL) impaired passive avoidance and facilitated two-way avoidance, effects similar to those observed in animals with limbic forebrain lesions. However, subsequent work indicated that TEL did not affect working memory as determined by performance in the radial-arm maze. Comparisons of trimethyl lead (TML) with TEL indicated that they produce quantitatively different behavioral effects, possibly due to toxicokinetic factors leading to differential neuromorphological changes in the CNS. Neurochemical studies indicated that TEL, TML and triethyl tin (TET) had few specific effects, but trimethyl tin (TMT) produced a pattern of neurochemical changes indicative of hyperammoniaemia. Although it is evident that TEL is not a limbitoxicant, other experiments demonstrated that it did produce specific alterations in neurobehavioral function (antinociception, increased responsiveness to pharmacological challenge) related to corresponding changes in neurochemical function (receptor binding, increased enzyme activity). Experiments with other potential limbitoxicants such as intracerebral administration of AF64A, a cholinergic cytotoxicant, produced signs of limbic forebrain dysfunction which were associated with decreases in acetylcholine (ACh) content in the hippocampus and frontal cortex. Destruction of granule cells in the dentate gyrus with colchicine produced similar behavioral effects. These studies indicate that cytotoxicants such as AF64A and colchicine may be useful in the study of neurodegenerative diseases involving limbic forebrain function.
