COGNITIVE ENHANCERS IN THEORY AND PRACTICE - STUDIES OF THE CHOLINERGIC HYPOTHESIS OF COGNITIVE DEFICITS IN ALZHEIMERS-DISEASE

The current status of the cholinergic hypothesis of cognitive dysfunct ion in Alzheimer's disease is reviewed in the context of recent attemp ts to alleviate specific cognitive impairments produced in rats by exc itotoxic lesions of basal forebrain neurons by treatment with choliner gic agents. AMPA-induced lesions of the nucleus basalis region in rats produce profound and relatively specific reductions in neocortical ma rkers of cholinergic function but fail to affect performance in many t ests of memory and learning in rats. However, such lesions produce spe cific deficits in responding accurately in a test of visual attentiona l performance, which are reversed dose-dependently by treatment with s ystemic physostigmine or nicotine. Analogous improvements have been re ported in a clinical trial of the anticholinesterase tacrine in patien ts with Alzheimer's disease. By contrast, AMPA-induced lesions of the medial septum produce profound reductions in hippocampal acetylcholine and accompanying delay-dependent deficits in a delayed non-matching-t o-position procedure which measures spatial working memory in rats. Th is impairment is shown to be reversed to some extent by treatment with low doses of physostigmine. The results are discussed in terms of the multivariate nature of the neurochemical pathology of Alzheimer's dis ease and attendant limitations in the use of the cholinergic strategy. The cognitive costs, as well as benefits, of cognitive enhancers are discussed, as well as the need to broaden our therapeutic approach to other neurotransmitter systems and other neurodegenerative disorders.