PSYCHOPHARMACOLOGICAL EFFECTS OF EXOGENOUS CHOLINE

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Our ability to understand and treat some behavioral disorders has benefitted greatly from our expanding knowledge about the biochemistry and pharmacology of monoamine neurotransmitters. Although abundant evidence indicates that brain acetylcholine (ACh) is also involved in behavioral diseases, much less basic information is available about this transmitter, and few if any drugs exists which can be given chronically to enhance cholinergic CNS transmission. Our proposal studies focus on a poorly- understood and perhaps-unique aspect of cholinergic neurons, i.e., their use of choline as a precursor for both ACh and such membrane phospholipids as phosphatidylcholine (PC; lecithin). We and others previously showed that supplemental choline could increase the syntheses of both ACh (particularly in frequently- firing neurons) and phosphocholine (an intermediate in PC synthesis). More recent studies have shown that the choline in neuronal PC is, in fact, used for ACh synthesis, and that, when choline is in short supply, the brain used it for this purpose preferentially, at the expense of membrane phospholipids. When superfused slices of rat striatum were depolarized repeatedly without adequate external choline, this PC was depleted, and most of its choline content would be accounted for by released ACh. Moreover, the other major membrane phospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), as well as membrane proteins, also were depleted, suggesting a relationship between neuronal depolarization and membrane levels. These reductions could all be blocked (and ACh release enhanced) by adding adequate choline to the medium. Moreover, choline's actions may be potentiated by cytidine or 4-aminopyridine, and its incorporation into neuronal PC enhanced by PS. Proposed studies examine the biochemical mechanisms, tissue distribution, and functional consequences of these changes in membrane phospholipids, using cholinergic cells lines (LAN-2; NG 108-15; PC-12), superfused rat brain slices, synaptosomes, and whole animals. We will also continue studies (on human brain samples) which suggest that related abnormalities occur in Alzheimer's disease, and will determine whether psychotropic drugs (which can cause tardive dyskinesia) affect PC metabolism in cholinergic neurons.