Inhibition of butyrylcholinesterase improves prepulse inhibition deficits and enhances M1 muscarinic acetylcholine receptor-mediated responses via ghrelin signaling in mice

[Speaker] Shinji Tsukada:1
[Co-author] Kosuke Higashino:1, Sumiko Kunimoto:1, Nigel H. Greig:2, Toshio Matsuda:1, Hitoshi Hashimoto:1,3,4, Yukio Ago:1
1:Graduate School of Pharmaceutical Sciences, Osaka University, Japan, 2:Translational Gerontology Branch, National Institute on Aging, NIH, USA, 3:United Graduate School of Child Development, Osaka University, Japan, 4:Institute for Datability Science, Osaka University, Japan

[Background] Rivastigmine is an inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and is used in the symptomatic treatment of Alzheimer's disease, as are the AChE inhibitors donepezil and galantamine. We previously found that these AChE inhibitors alleviate deficits in prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activation of M1 muscarinic ACh (mACh) receptors in mice (Yano et al., Br J Pharmacol, 2009; Higashino et al., Psychopharmacology, 2016). Rivastigmine increased extracellular ACh levels in the prefrontal cortex, although to a lesser degree than the other AChE inhibitors, galantamine and donepezil. Furthermore, rivastigmine enhanced M1 receptor-mediated responses in the brain, while galantamine or donepezil did not. These findings suggest that rivastigmine improves PPI deficits by enhancing mACh receptor function independent of AChE inhibition. Here we aimed to clarify whether BuChE inhibition improves PPI deficits and enhances mACh receptor function in mice.
[Methods] All animal studies were approved by the Animal Care and Use Committee of the Graduate School of Pharmaceutical Sciences, Osaka University. Eight-week-old male ddY outbred mice were used. Extracellular ACh and dopamine levels in the prefrontal cortex were measured by in vivo microdialysis. Acoustic startle responses and PPI were measured in a startle chamber.
[Results] The selective BuChE inhibitor tetraisopropyl pyrophosphoramide (iso-OMPA) improved apomorphine-induced PPI deficits, and it increased extracellular ACh levels only by approximately 2-3-fold. The preferential M1 receptor agonist N-desmethylclozapine increased prefrontal dopamine release, and this effect was blocked by the M1 receptor antagonist telenzepine, suggesting a marker of mACh receptor function. Iso-OMPA and the other selective and potent BuChE inhibitor (-)-N1-phenethylnorcymserine (PEC) enhanced N-desmethylclozapine-induced dopamine release, and telenzepine also blocked the effect of PEC. BuChE is known to modulate ghrelin's biological functions by cleaving the peptide's n-octanoyl group, leaving an inactive desacyl peptide. Then, the ghrelin receptor antagonist JMV2959 inhibited the enhancement of prefrontal dopamine release induced by PEC as well as rivastigmine.
[Conclusion] These results suggest that BuChE inhibition, like rivastigmine, enhances M1 receptor function in the brain and improves PPI deficits. Activation of ghrelin signaling through inhibiting BuChE might be involved in the enhancement of mACh receptor function.

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