Preclinical experiments on cognition enhancement in Alzheimer's disease: Drugs affecting nicotinic acetylcholine receptors

Abstract

AbstractNicotinic acetylcholine receptors (nAChRs) play a role in a variety of diseases of the central nervous system including Alzheimer's disease (AD). There is currently great interest in evaluating AD‐related nAChR changes, and pharmacological treatment of nAChR deficits is a promising therapy. In AD, α7 nAChRs remain relatively stable in contrast to α4β2 nAChRs that are lost in substantial numbers. However, α7 nAChRs may be functionally impaired in AD because β‐amyloid, a major neuropathology in AD, blocks α4β2 and α7 nAChRs. Agonists selective to α7 or α4β2 nAChRs are neuroprotective against β‐amyloid. A preclinical test of cognition‐enhancing drugs affecting nAChRs is eyeblink classical conditioning. This task is severely impaired in human probable AD patients and is impaired by antagonists to nAChRs. Three drugs with different mechanisms of action on nAChRs (partial α7 nAChR agonism [GTS‐21], acetylcholinesterase inhibition and allosteric modulation [galantamine], nootropic activation [nefiracetam]) were tested in young and older rabbits using eyeblink classical conditioning. All three drugs ameliorated learning and memory impairments in older rabbits and reversed an antagonist to nAChRs in young rabbits. Galantamine, with its allosteric modulatory action, was the only drug that facilitated learning in young rabbits. On the basis of efficacy of these drugs that affect nAChRs in preclinical studies and in Phase I (GTS‐21), Phase II (nefiracetam), or Phase III (galantamine) clinical trials, exploration of nAChRs as targets for therapeutic intervention via a number of different pathways seems warranted. Drug Dev. Res. 56:335–346, 2002. © 2002 Wiley‐Liss, Inc.