The purpose of this research program is to develop: 1) animal models of cognitive dysfunction using neurotoxicants as tools to mimic specific aspects of neurological diseases known to exist in humans, and 2) strategies for the treatment and/or prevention of neurodegenerative processes. Cognitive dysfunction is frequently associated with cholinergic hypofunction or damage to the limbic forebrain; cytotoxicants were administered directly into the brain to mimic these processes. Injection of AF64-A, a purported cholinergic cytotoxicant, produced behavioral effects indicative of cholinergic dysfunction in rats, including hyperactivity and deficits in spatial learning. However, other studies indicate that this agent may have direct effects on other neurotransmitter or neuromodulator systems. However, direct administration of cholchicine into the hippocampus caused preferential damage to the granule cells and mossy fibers of the dentate gyrus. These alterations were associated with deficits in spatial learning and acquisition and retention of an avoidance task and increased sensitivity to challenge with scopolamine, a muscarinic receptor antagonist. Preliminary studies showed that behavioral and histopathological damage produced by colchicine was attenuated by pretreatment with gangliosides. Future studies will: 1) replicate and extend the finding that gangliosides protect against the effects produced by colchicine, as well as those produced by another cytotoxicant such as 6-hydroxydopamine, 2) determine possible restorative effects of gangliosides, 3) investigate other models of cognitive dysfunction such as the effects of administration of ibotinec acid into the nucleus basalis of Meynert, and 4) evaluate pharmacological agents such as physostigmine and analogues of arecoline as to their potential activity against colchicine-induced degeneration of the hippocampus.
