POSSIBLE ROLE OF THE CHOLINERGIC SYSTEM AND DISEASE-MODELS

Memory impairment associated with the loss of cortical cholinergic neu rons in AD has stimulated the development of animal models based on bl ockade or destruction of these systems. Strategies include mechanical lesions, local injection of excitotoxic amino acids or ethylcholine az iridinium (AF 64A), which disrupt reference and working memory in rats , but lack specificity for cholinergic systems. Other models involving , reduction in cerebral blood flow and interference with oxidative met abolism of glucose, mimic those found in AD, and also interfere with w orking and long-term memory in the rat. Memory impairments can be reve rsed by acetylcholinesterase inhibitors and cholinergic agonists but b eneficial effects of these agents in AD patients are small and inconsi stent. This may be partly due to unfavorable pharmacokinetics and dose -limiting side effects of existing drugs. Newer, brain specific acetyl cholinesterase inhibitors and M1 muscarinic agonists with a lower inci dence of unwanted effects are currently being evaluated.