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Received for publication March 2, 2004.
Revised May 10, 2004.
Accepted for publication June 17, 2004.
Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in cognition, and may play a role in Alzheimer's disease (AD). Known inhibitors of acetylcholinesterase (AChE) are used to treat AD, and are known cognitive enhancers, however their mechanism of action relating to AD is not fully understood. We tested several AChE inhibitors, including huperzine A, tacrine, and BW284c51, on nAChRs in rat hippocampal CA1 interneurons in slices using patch-clamp techniques. These interneurons express both 
7 and non-7 subunit-containing nAChRs, and were activated with pressure applications of ACh, choline, or carbachol. These AChE inhibitors had no significant effect on either the amplitude or kinetics of 7 nAChRs activated by ACh, but slowed the rate of recovery from desensitization through an indirect mechanism; responses activated with either choline or carbachol were unaffected. For non-7 receptors, these inhibitors significantly increased the amplitude and decay phase for responses induced by ACh (but not carbachol), also through an indirect mechanism. Slices preincubated with diisopropylflurophosphate (DFP; to permanently inactivate AChE) mimicked the effect of these AChE inhibitors on both 7 and non-7 nAChRs. In addition galantamine, which is both an inhibitor of AChE and an allosteric potentiator of nAChRs, had similar effects. Therefore various AChE inhibitors are having significant and indirect effects on nAChRs, through direct inhibition of AChE; this results in an enhanced amount and/or duration of ACh in slices, with no effect on the levels of choline or carbachol. Therefore, drugs that target AChE are likely to be important regulators of cholinergic signaling in the hippocampus.
Key words:
Nicotinic cholinergic, Ion channel regulation, Func. analysis receptor/ion channel mutants, Synaptic plasticity
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