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      Physiological roles of CNS muscarinic receptors gained from knockout mice

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          Abstract

          Because the five muscarinic acetylcholine receptor subtypes have overlapping distributions in many CNS tissues, and because ligands with a high degree of selectivity for a given subtype long remained elusive, it has been difficult to determine the physiological functions of each receptor. Genetically engineered knockout mice, in which one or more muscarinic acetylcholine receptor subtype has been inactivated, have been instrumental in identifying muscarinic receptor functions in the CNS, at the neuronal, circuit, and behavioral level. These studies revealed important functions of muscarinic receptors modulating neuronal activity and neurotransmitter release in many brain regions, shaping neuronal plasticity, and affecting functions ranging from motor and sensory function to cognitive processes. As gene targeting technology evolves including the use of conditional, cell type specific strains, knockout mice are likely to continue to provide valuable insights into brain physiology and pathophysiology, and advance the development of new medications for a range of conditions such as Alzheimer’s disease, Parkinson’s disease, schizophrenia, and addictions, as well as non-opioid analgesics.

          This article is part of the special issue entitled ‘Muscarinic Receptors in the Central Nervous System’.

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          Most cited references141

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          Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior.

          Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development.

            Muscarinic acetylcholine receptors (mAChRs), M(1)-M(5), regulate the activity of numerous fundamental central and peripheral functions. The lack of small-molecule ligands that can block or activate specific mAChR subtypes with high selectivity has remained a major obstacle in defining the roles of the individual receptor subtypes and in the development of novel muscarinic drugs. Recently, phenotypic analysis of mutant mouse strains deficient in each of the five mAChR subtypes has led to a wealth of new information regarding the physiological roles of the individual receptor subtypes. Importantly, these studies have identified specific mAChR-regulated pathways as potentially novel targets for the treatment of various important disorders including Alzheimer's disease, schizophrenia, pain, obesity and diabetes.
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              Muscarinic acetylcholine receptors: novel opportunities for drug development.

              The muscarinic acetylcholine receptors are a subfamily of G protein-coupled receptors that regulate numerous fundamental functions of the central and peripheral nervous system. The past few years have witnessed unprecedented new insights into muscarinic receptor physiology, pharmacology and structure. These advances include the first structural views of muscarinic receptors in both inactive and active conformations, as well as a better understanding of the molecular underpinnings of muscarinic receptor regulation by allosteric modulators. These recent findings should facilitate the development of new muscarinic receptor subtype-selective ligands that could prove to be useful for the treatment of many severe pathophysiological conditions.
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                Author and article information

                Journal
                0236217
                6077
                Neuropharmacology
                Neuropharmacology
                Neuropharmacology
                0028-3908
                1873-7064
                16 September 2017
                11 September 2017
                01 July 2018
                01 July 2019
                : 136
                : Pt C
                : 411-420
                Affiliations
                [a ]Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen and University of Copenhagen, Denmark
                [b ]Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
                Author notes
                Corresponding author: Morgane Thomsen, Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark, mthomsen@ 123456mclean.harvard.edu
                Article
                PMC5845799 PMC5845799 5845799 nihpa906687
                10.1016/j.neuropharm.2017.09.011
                5845799
                28911965
                0400df49-5a7b-4bb4-a7dd-4d198ad0ba15
                History
                Categories
                Article

                knockout,mice,null mutation,knock-out,cholinergic,muscarinic
                knockout, mice, null mutation, knock-out, cholinergic, muscarinic

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