The purpose of this research program is to develop in rats models of neurodegeneration using neurotoxicants to mimic features of neurological disorders, such as Alzheimer's Disease (AD). Microinfusion of colchicine, a neurotoxicant that binds to tubulin and disrupts assembly of microtubules, into the hippocampus, an area known to degenerate in AD, destroys dentate gyrus granule cells and mossy fibers preferentially and disrupts the acquisition and retention of working and reference memory only if it is performed in a spatial context. Working or short-term memory is affected early in AD, while reference for long-term memory is affected late in AD. These data indicate the importance of the hippocampus for memory particularly if performed in a spatial context. Infusion of colchicine into the nucleus basalis, an area containing cell bodies for cholinergic neurons that project to the cortex and known to degenerate in AD, disrupted the acquisition and retention of spatial, working memory; reference memory was not affected. Further characterization of the colchicine effect revealed a relatively localized destruction of cells in the nucleus basalis which was associated with a regionally specific decrease in cholineacetyltransferase activity in the cortex. Receptor binding studies found decrease in presumably presynaptic nicotinic receptors, while post-synaptic muscarinic receptors were not affected. Recent studies have shown that overexcitation of receptors for excitatory amino acid neurotransmitters can result in neurotoxicity and has been suggested as a possible etiological factor in AD. Microinfusion of N-MDA into the hippocampus produced dose-dependent loss of neurons and deficits in a spatial reference memory task. These effects could be blocked by pretreatment with MK-801, a noncompetitive receptor blocker for N-MDA receptors. These results indicate the potential usefulness of agents such as MK-801 as possible therapeutic agents for neurodegenerative disorders.
