Effects of Postnatal Trimethyltin or Triethyltin Treatment on CNS Catecholamine, GABA, and Acetylcholine Systems in the Rat

Abstract

The effects on brain neurochemistry of two neurotoxic tin compounds, trimethyltin (TMT) hydroxide and triethyltin (TET) sulfate, were examined. Long-Evans rats were treated with TMT hydroxide (1 mg/kg, i.p.) on alternate days from day 2 to 29 of life. These treatments caused a weight deficit of 10-20% by the time the animals were killed on day 55 by head-focused microwave irradiation. These TMT treatments are known to cause severe neuronal loss in the hippocampus and lesser damage in other brain regions. Accordingly, the concentration of gamma-aminobutyric acid (GABA) was decreased in the hippocampus; however, acetylcholine and choline concentrations were unaffected. These data suggest that TMT-induced effects on GABA systems are greater than that due simply to generalized neuronal loss. The TMT treatments also caused a significant decrease in dopamine concentrations in the striatum, but did not alter the concentrations of dihydroxyphenylacetic acid or homovanillic acid, the acidic metabolites of dopamine. Conversely, concentrations of dopamine and norepinephrine in the brain stem and norepinephrine in the cerebellum were not altered. Despite reports in the literature of TMT-induced neuronal damage in areas of the cortex, no effects on GABA, acetylcholine, or choline levels were found in the cortical areas examined, or in the hypothalamus. TET sulfate (0.3 mg/kg/day) was administered for 6 consecutive days of every week during days 2-29 of life. This dose is lower than that needed to cause intramyelin edema, yet it does result in long-term behavioral changes. Despite this, no changes in the concentration of any of the measured neurotransmitters or their metabolites were detected. In concert, these data demonstrate that neurochemical methods should not be used as neurological "screens," but rather to define specific mechanisms suggested by detailed behavior, pharmacological, and/or physiological studies.

Effect of trimethyltin on ornithine decarboxylase in various regions of the mouse brain

“…This regional selectivity has been confirmed in studies of neurotransmitter-related parameters [9][10][11] and provides the opportunity to examine for metabolic changes in various brain areas after exposure of animals to TMT. Ornithine decarboxylase (ODC), the rate limiting enzyme of polyamine synthesis, is capable of rapidly responding in cerebral tissues that have been activated or damaged [12][13][14].…”

Trimethyltin Stimulates Protein Kinase C Translocation Through Receptor‐Mediated Phospholipase C Activation in PC12 Cells

“…Numerous studies have described perturbations in neurotransmitter systems and neurotransmitter release following TMT exposure. These include the cholinergic (O' Connell et al, 1994a,b), glutamatergic (Patel et al, 1990), GABAergic (Brodie et al, 1990), dopaminergic (Mailman et al, 1983), and serotoninergic (Earley et al, 1992) neurotransmitter systems. However, the mechanism of TMT-stimulated neurotransmitter release and its contribution to TMT-mediated cytotoxicity have not been clearly established.…”

Metal toxicity at the synapse: presynaptic, postsynaptic and long-term effects

“…These changes in uptake of neurotransmitters could explain their altered levels in the synaptic cleft [110]. However, unlike trimethyl tin, triethyl tin sulfate had no effect on the levels of dopamine, GABA or acetylcholine in rat brain on exposure for 6 days a week from days 2 to 29 of life in mice [107].…”

“…Among organic metals, trimethyl tin hydroxide treatment of rats on alternate days from days 2-29 of life was shown to decrease the amount of dopamine in the striatum without affecting dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid [107].…”