Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

December 1992

Abstract

Trimethyltin (TMT) is a neurotoxin occurring in the environment. Exposure to (TMT) is known to destroy specific neuronal components of the hippocampus in the rat and to cause clinical symptoms in exposed humans, including mnemonic deficits, that indicate hippocampal involvement. In addition to hippocampal cell loss TMT causes significant increases in cholinergic markers such as acetylcholinesterase (AChE) stain density and choline acetyltransferase (ChAT) activity in the hippocampus of rats. However, despite these observations the effect of TMT on hippocampal cholinergic system has not been investigated in detail. The purpose of the present study was to elucidate more fully the consequences of TMT administration on the rat cholinergic system. To this end the effects of increasing doses of TMT and time after TMT administration on choline acetyltransferase (ChAT) activity as well as TMT's effect on cholinergic muscarinic receptors was examined. Results indicate that 4 and 6 mg/kg doses of TMT measurable neuropathological effects on pyramidal cells of the hippocampus. ChAT activity was increased in the hippocampus as a result of the 6 mg/kg dose. Six mg/kg TMT was observed to affect morphology differentially over time, with the various sub-fields examined being affected at different time intervals. The effect of time on increased ChAT activity after TMT-treatment was observed in the dentate gyrus prior to the CA1 region. The effect of 6 mg/kg TMT on muscarinic receptor distribution over time is first observed in CA1 and CA3c then CA3a-b of the subtype M$\sb2$. The subtype M$\sb1$ receptors are also affected in these regions but at later time intervals. The total distribution of muscarinic receptors is reduced in regions CA1 and CA3c. This is observed at similar time intervals as for M$\sb1$ receptors. The conclusions made as a result of these findings are: (1) That TMT's effect on ChAT activity and morphology of the rat hippocampus is both dose and time dependent; (2) That adverse effects of TMT on ChAT activity and morphology in sub-regions of the hippocampus are observed at different time intervals; and (3) That the distribution of the muscarinic receptors examined are affected by TMT in a regional manner dependent upon the time following administration of TMT.

Document Type

Dissertation - unrestricted

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