This renewal application focuses on regulation of muscarinic acetylcholine receptors (mAChR) and novel therapeutic approaches to cholinergic involvement in common neuropsychiatric symptoms of human neurological diseases. Cholinesterase inhibitors are the main cholinomimetics available for clinical use, but are only modestly effective and frequently cause adverse effects. Cholinesterase inhibitors act indiscriminately on all members of the mAChR family (M1-M5), but recent evidence suggests that drugs targeted to individual receptor subtypes will be more effective and have fewer side effects. Remarkably, there is also evidence that activation of mAChR subtypes may influence the neuropathology and progression of Alzheimer's disease (AD). The goal of advancing cholinergic therapies through targeting mAChR subtypes has been hampered by several factors, including lack of highly selective drugs, poor understanding of the roles of individual receptors, limited availability of mouse models, and adaptive mechanisms that limit responsiveness during chronic stimulation. However, we and others have made exciting progress overcoming these limitations. This proposal capitalizes on recent progress to test the central hypothesis that activation and antagonism of central M1 receptors play opposing roles in AD.
Three Specific Aims will 1) characterize novel drugs that selectively activate M1, 2) evaluate the effects of non-specific and M1-specific cholinomimetics on amyloidogenesis, and 3) evaluate the role of mAChR subtypes in mediating anticholinergic effects and modulating the progression of AD. In order to achieve these Aims, we will employ a blend of pharmacologic approaches using drugs with distinct actions on mAChR, and genetic approaches using transgenic mouse models of amyloidogenesis and knock out mice deficient in individual mAChR subtypes. The results of these studies should substantially advance the goal of developing more effective cholinergic therapies for AD and other neuropsychiatric disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
Lebois, Evan P; Schroeder, Jason P; Esparza, Thomas J et al. (2017) Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model. ACS Chem Neurosci 8:1177-1187
Davis, Albert A; Heilman, Craig J; Brady, Ashley E et al. (2010) Differential effects of allosteric M(1) muscarinic acetylcholine receptor agonists on receptor activation, arrestin 3 recruitment, and receptor downregulation. ACS Chem Neurosci 1:542-551
Davis, Albert A; Fritz, Jason J; Wess, J├╝rgen et al. (2010) Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. J Neurosci 30:4190-6
Shirey, Jana K; Brady, Ashley E; Jones, Paulianda J et al. (2009) A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J Neurosci 29:14271-86
Cabadak, Hulya; Cuadra, Adolfo E; El-Fakahany, Esam E et al. (2009) M2, M3, and M4 muscarinic receptors are expressed in the guinea pig gallbladder. J Recept Signal Transduct Res 29:63-6
Bazalakova, M H; Wright, J; Schneble, E J et al. (2007) Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. Genes Brain Behav 6:411-24
McClatchy, Daniel B; Fang, Guofu; Levey, Allan I (2006) Elongation factor 1A family regulates the recycling of the M4 muscarinic acetylcholine receptor. Neurochem Res 31:975-88
Bernstein, Leah S; Ramineni, Suneela; Hague, Chris et al. (2004) RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling. J Biol Chem 279:21248-56
Li, Bin; Duysen, Ellen G; Volpicelli-Daley, Laura A et al. (2003) Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice. Pharmacol Biochem Behav 74:977-86
Ferguson, Shawn M; Savchenko, Valentina; Apparsundaram, Subbu et al. (2003) Vesicular localization and activity-dependent trafficking of presynaptic choline transporters. J Neurosci 23:9697-709

Showing the most recent 10 out of 51 publications