PT  - JOURNAL ARTICLE
AU  - Dmitriy Fayuk
AU  - Jerrel L. Yakel
TI  - Regulation of Nicotinic Acetylcholine Receptor Channel Function by Acetylcholinesterase Inhibitors in Rat Hippocampal CA1 Interneurons
AID  - 10.1124/mol.104.000042
DP  - 2004 Sep 01
TA  - Molecular Pharmacology
PG  - 658--666
VI  - 66
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/66/3/658.short
4100  - http://molpharm.aspetjournals.org/content/66/3/658.full
SO  - Mol Pharmacol2004 Sep 01; 66
AB  - 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 1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide (BW284c51), on nAChRs in rat hippocampal CA1 interneurons in slices using patch-clamp techniques. These interneurons express both α7 and non-α7 subunit-containing nAChRs and were activated with pressure applications of acetylcholine (ACh), choline, or carbachol. These AChE inhibitors had no significant effect on either the amplitude or kinetics of α7 nAChRs activated by ACh, but they slowed the rate of recovery from desensitization through an indirect mechanism; responses activated with either choline or carbachol were unaffected. For non-α7 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 (to permanently inactivate AChE) mimicked the effect of these AChE inhibitors on both α7 and non-α7 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.