The major objectives of the proposed research are to develop nontraumatic methods with which to study central nervous system (CNS) cholinergic function in man, and to explore the extent of cholinergic involvement in a variety of mental and neurological disease states. Three parallel lines of investigation will be followed: I. We will continue to explore the relevance of elevated choline (Ch) values and of reduced Ch transport, which we have found in red blood cells (RBC) of certain depressed patients, in Gilles de la Tourette's Syndrome, and in bipolar individuals treated with lithium carbonate. In vivo and in vitro studies are planned, aimed at exploring RBC-membrane related factors which may be responsible for these findings. Laboratory data will be correlated with clinical change; sleep-EEG change; response to treatment with various antidepressants, lithium and lecithin; and genetic predisposition to the clinical state. II. We have shown that one can achieve effective labelling of mouse brain acetylcholine (ACh) and Ch by supplying deuterium labelled Ch in the diet. An excellent correlation exists between the incorporation of Ch in the CNS, brain ACh synthesis, and reflected changes in Ch pools in plasma and RBCs. An extensive protocol has been outlined in this application utilizing kinetic, genetic, and pharmacological approaches, aimed at determining the reliability of this animal model, and establishing to what extent it may be useful in predicting central cholinergic function, using peripheral neurochemical indices from blood. III. The effect of precursor loading with different orally administered preparations of lecithin on central cholinergic function will be explored in rats. A systematic analysis of timetable of administration, type of lecithin preparation administered, and mode of administration, will be conducted. Particular emphasis will be placed on evaluating a new (Thomas J. Lipton Co.) edible lecithin product on the market. Intentionally, there is considerable overlap in these proposed experiments. They have been designed to employ a multifaceted, coordinated research strategy, using both clinical and basic approaches. Their ultimate goal is to achieve a better understanding of the nature and extent of involvement of cholinergic mechanisms in mental disease states.
