The goal of this project is to develop improved pharmaceutical therapies for central nervous system disease based on the relation between transmitter mechanisms and clinical function. Investigations focus on the dopamine system and closely interactive neural pathways as they relate to dementing and extrapyramidal disorders. The search for transmitter abnormalities which serve as critical determinants for Alzheimer dementia has yielded evidence casting doubt on the importance of cholinergic system abnormalities: choline acetyltransferase reductions were no greater in the parietal association cortex, where positron emission tomography shows maximum cortical dysfunction, than in the relatively spared frontal lobe. Moreover, treatment with maximum tolerated doses of a potent muscarinic agonist failed to improve cognitive performance. On the other hand, somatostatin levels were mainly reduced in the posterior parietal cortex. Neuropeptide Y, which is partially co-localized with somatostatin, was not abnormal in any cortical area. Motor fluctuations, which ultimately occur in most levodopa treated parkinsonian patients, probably do not reflect changes in peripheral clearance mechanisms but rather drug induced alterations in central pharmacodynamic factors. Both mechanical (wearable infusion pumps) and pharmaceutical (sustained release formulations) means for stabilizing plasma dopa levels are proving effective in attenuating these response fluctuations. Many of the centrally mediated pharmacological effects of peripherally administered cholecystokinin-octapeptide (CCK-8) and related peptides in rodents now appear to reflect stimulation of vagal afferents. The peripheral injection of CCK-8 analogs has, nevertheless, proven therapeutically ineffective in nonvagotomized patients. Alternate strategies for influencing central cholecystokininergic mechanisms are thus being explored, including the development of relatively lipophilic compounds to inhibit the metaloendopeptidase found responsible for initial CCK-8 degradation.
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