The purpose of this research is to: 1) develop animal models of neurodegeneration using neurotoxicants to mimic neurological disorders, with an emphasis on understanding the adaptive and compensatory changes associated with insult to the nervous system, 2) establish neurobiological principles concerning restoration of function. Intradentate hippocampal infusion of colchicine causes dose- and time-dependent loss of granule cells and mossy fibers, decreases in neuropeptides and deficits in spatial, short-term memory. We also found that the memory deficits observed in colchicine-treated rats were attenuated by cholinomimetics, agents reported to be effective in some patients with Alzheimer's Disease (AD). Noncholinnergic agents, such as naloxone, piracetam and vasopressin had no effect. Colchicine-treated rats were also less sensitive to the pharmacological effects of scopolamine, a muscarinic receptor antagonist; this effect was associated with an increase in a presynaptic marker for acetylcholine and a decreased number of muscarinic receptors in the hippocampus, suggesting a cholinergic hyperinnervation. In an attempt to promote regeneration or reactive synaptogenesis, direct application of neurotrophic factors such as nerve growth factor or gangliosides at the time of lesion did not affect colchicine-induced damage. In other studies, a suspension of undifferentiated fetal hippocampal cells was injected into the hippocampus of colchicine-treated rats and an attenuation of colchicine-induced behavioral effects was observed. Colchicine injected into the nucleus basalis, an area known to be affected in AD, also produced deficits in learning and memory, which were associated with a loss of a presynaptic cholinergic marker in the frontal cortex. The performance of these rats was also improved by cholinergic agents. We plan to investigate the conditions necessary to reestablish connections following implantation of undifferentiated cells into damaged areas and, because of the observed hyperinnervation, to determine changes in cholinergic stimulation of phosphoinositol metabolism in lesioned areas of the central nervous system.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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U.S. National Inst of Environ Hlth Scis
United States
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