Dysfunctional presynaptic M2 receptors in the presence of chronically high acetylcholine levels : data from the PRiMA knockout mouse

  • The muscarinic M2 receptor (M2R) acts as a negative feedback regulator in central cholinergic systems. Activation of the M2 receptor limits acetylcholine (ACh) release, especially when ACh levels are increased because acetylcholinesterase (AChE) activity is acutely inhibited. Chronically high ACh levels in the extracellular space, however, were reported to down-regulate M2R to various degrees. In the present study, we used the PRiMA knockout mouse which develops severely reduced AChE activity postnatally to investigate ACh release, and we used microdialysis to investigate whether the function of M2R to reduce ACh release in vivo was impaired in adult PRiMA knockout mice. We first show that striatal and hippocampal ACh levels, while strongly increased, still respond to AChE inhibitors. Infusion or injection of oxotremorine, a muscarinic M2 agonist, reduced ACh levels in wild-type mice but did not significantly affect ACh levels in PRiMA knockout mice or in wild-type mice in which ACh levels were artificially increased by infusion of neostigmine. Scopolamine, a muscarinic antagonist, increased ACh levels in wild-type mice receiving neostigmine, but not in wild-type mice or in PRiMA knockout mice. These results demonstrate that M2R are dysfunctional and do not affect ACh levels in PRiMA knockout mice, likely because of down-regulation and/or loss of receptor-effector coupling. Remarkably, this loss of function does not affect cognitive functions in PRiMA knockout mice. Our results are discussed in the context of AChE inhibitor therapy as used in dementia.

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Author:Franziska MohrGND, Eric Krejci, Martina Zimmermann, Jochen KleinORCiDGND
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/26506622
Parent Title (English):PLoS One
Place of publication:Lawrence, Kan.
Document Type:Article
Date of Publication (online):2015/10/27
Date of first Publication:2015/10/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/02/03
Issue:(10): e0141136
Page Number:13
First Page:1
Last Page:13
Copyright: © 2015 Mohr et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0