Our ability to understand some mental diseases, and to develop effective drugs for treating the diseases, has benefitted greatly from our expanding knowledge about the biochemistry and pharmacology of the monoamine neurotransmitters. Although abundant evidence indicates that brain acetylcholine [ACh] is also involved in some diseases affecting behavior, considerably less basic information is available about this transmitter, and few if any therapeutic agents now exist which can be used chronically to enhance cholinergic CNS transmission. The studies described in this renewal application will examine a perhaps unique aspect of cholinergic neurons, i.e., their use of choline for two purposes: As the precursor for their neurotransmitter, and as a constituent of their membrane phospholipids (principally, phosphatidylcholine [PC; lecithin]). We and others previously showed that giving supplemental choline could increase the syntheses of both ACh (particularly, in frequently-firing neurons) and phosphorylcholine (a limiting intermediate in the major pathway for PC synthesis). We now wish to examine the inverse possibility -- that when inadequate choline is available for ACh synthesis, cholinergic neurons obtain more of it by hydrolyzing PC in their membranes. We will use, primarily, two experimental systems developed here during the past two years: Cultured cells that produce ACh and PC, and electrically-stimulated slices of superfused rat caudate nucleus. We will also determine whether a particular """"""""pool"""""""" of PC, which can be differentiated from the others by its mode of synthesis [e.g., phosphatidylethanolamine methylation; base-exchange; CDP-choline cycle], or by its fatty acid composition, is used preferentially as a choline source. Related studies will determine whether supplemental choline, given in doses that promote the release of acetylcholine, also """"""""protects"""""""" brain PC from being hydrolyzed as a choline source, and whether various psychopharmacologic agents, particularly, those believed to affect cholinergic transmission, alter the metabolism of choline or PC. If the processes controlling ACh synthesis and release are intertwined with those affecting membrane composition (e.g., PC levels in relation to those of other membrane components), then rational long-term therapies for diseases involving cholinergic transmission may need to be directed to both the ACh and the membranes.
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