Regulation of nicotinic acetylcholine receptor channel function by acetylcholinesterase inhibitors in rat hippocampal CA1 interneurons.
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 alpha7 and non-alpha7 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 alpha7 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-alpha7 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 alpha7 and non-alpha7 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.
Fayuk
Dmitriy
D
National Institute of Environmental Health Scinces, F2-08, P.O. Box 12233, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Yakel
Jerrel L
JL
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D005702:Galantamine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism; D007531:Isoflurophate / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D005702:Galantamine; D007531:Isoflurophate