A deficiency in brain acetylcholine (ACh) function has been implicated in a variety of neurologic and psychiatric disorder. If one were to develop an animal model in which one could simulate the neurochemical conditions which appear to cause these diseases in humans, it would then be feasible to explore mechanisms with which to reverse the situation and to alleviate, and possibly even cure, the specific disease states. This would require the availability of chemical agents which would selectively be taken up in cholinergic nerve terminals, and would subsequently permanently disturb the normal equilibrium of synthetic processes in these nerve terminals. Experiments proposed for the continued support will follow three parallel and integrated lines of research. 1) We will continue to explore the potential of AF64A as an animal model of Alzheimer's disease (AD), and will use it as a probe to attempt to answer mechanistic questions of relevance to cholinergic function in vivo. 2) In addition, a series of new chemical analogs of choline will be synthesized according to specific rationales for their affinity for cholinergic nerve terminals and/or postsynoptic ACh receptors. Following their synthesis the compounds will be screened intensively in mice, rats and cats for their effect on cholinergic systems both in vitro and in vivo. Agents which show promise as potential cholinergic neurotoxins will then be evaluated for specificity toward the cholinergic system, by analyzing the interaction of these promising compounds with the catecholaminergic, serotonergic, and GABA-ergic systems. Histological verification of specific lesions, the effect of these compounds on phospholipid metabolism in brain; and their effects on memory and learning, utilizing sensitive and specific behavioral tests will follow in rats. Tissue cultures obtained from chicks will be utilized for a more extensive evaluation of some of the effects of compound cholinotoxocity, in vitro. 3) Finally, different treatment approaches to reverse AF64A induced cholinergic hypofunction will be tested, utilizing agents such as choline, lecithin, acetylcholinesterase inhibitors; directly acting muscarinic agonists; and combinations of some of these drugs. The outcome of this multiphasic approach will hopefully lead to the development of specific animal models for AD, and to a potential valuable therapy for this disorder.
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