Nicotinic treatment of Alzheimer's disease

Approximately 20 years after the formulation of the "cholinergic hypothesis " to explain the cognitive symptoms of Alzheimer's disease, cholinesterase therapy remains the mainstay of treatment for this disorder. Although parti ally effective, currently available agents have limited effects on cognitiv e function and long-term efficacy appears modest. Direct or indirect stimul ation of nicotinic cholinergic receptors may offer an additional therapeuti c strategy. Ongoing investigations of the molecular substructure of central nervous system nicotinic receptors, their accompanying pharmacology, and t he effects of nicotinic agents on cognitive function have suggested the pos sibility that nicotinic stimulation may have beneficial effects in Alzheime r's disease and other neuropsychiatric disorders. Studies from our laborato ry and others have explored the role of central nervous system nicotinic me chanisms in normal human cognitive and behavioral functioning as well as th eir role in Alzheimer's disease. Results from acute therapeutic trials with nicotine and novel nicotinic agents suggest that nicotinic stimulation in Alzheimer's disease patients can improve the acquisition and retention of v erbal and visual information and decrease errors in cognitive tasks, as wel l as improve accuracy and response time. Whether such results will translat e into improved clinical functioning remains to be fully tested. Developmen t of subtype-selective nicotinic agonists with an improved safety profile w ill enable long-term testing of the efficacy of nicotinic stimulation on co gnitive performance as well as potential cytoprotective effects. Direct or indirect (allosteric) modulation of nicotinic receptor function offers a ne w opportunity for Alzheimer's disease therapeutics. (C) 2001 Society of Bio logical Psychiatry.