Novel allosteric agonists of M 1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models

Gregory J. Digby, Meredith J. Noetzel, Michael Bubser, Thomas J. Utley, Adam G. Walker, Nellie E. Byun, Evan P. Lebois, Zixiu Xiang, Douglas J. Sheffler, Hyekyung P. Cho, Albert A. Davis, Natali E. Nemirovsky, Sarah E. Mennenga, Bryan W. Camp, Heather Bimonte-Nelson, Jacob Bode, Kimberly Italiano, Ryan Morrison, J. Scott Daniels, Colleen M. Niswender & 4 others Michael Olive, Craig W. Lindsley, Carrie K. Jones, P. Jeffrey Conn

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

M 1 muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer's disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M 1 receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Here we describe the characterization of two novel M 1 allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M 1 coupling to different signaling pathways including Ca 2+ and β-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M 1 to specific signaling pathways leads to selective actions on some but not all M 1-mediated responses in brain circuits. These novel M 1 allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M 1-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M 1 agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M 1 allosteric agonists can differentially regulate coupling of M 1 to different signaling pathways, and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis.

Original languageEnglish (US)
Pages (from-to)8532-8544
Number of pages13
JournalJournal of Neuroscience
Volume32
Issue number25
DOIs
StatePublished - Jun 20 2012

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Muscarinic Receptors
Animal Models
Aptitude
Pyramidal Cells
Central Nervous System Diseases
Brain
Amphetamine
Psychotic Disorders
Cognition
Schizophrenia
Alzheimer Disease
Learning
Therapeutics
beta-Arrestin 1
VU0364572
VU0357017

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Novel allosteric agonists of M 1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. / Digby, Gregory J.; Noetzel, Meredith J.; Bubser, Michael; Utley, Thomas J.; Walker, Adam G.; Byun, Nellie E.; Lebois, Evan P.; Xiang, Zixiu; Sheffler, Douglas J.; Cho, Hyekyung P.; Davis, Albert A.; Nemirovsky, Natali E.; Mennenga, Sarah E.; Camp, Bryan W.; Bimonte-Nelson, Heather; Bode, Jacob; Italiano, Kimberly; Morrison, Ryan; Scott Daniels, J.; Niswender, Colleen M.; Olive, Michael; Lindsley, Craig W.; Jones, Carrie K.; Jeffrey Conn, P.

In: Journal of Neuroscience, Vol. 32, No. 25, 20.06.2012, p. 8532-8544.

Research output: Contribution to journalArticle

Digby, GJ, Noetzel, MJ, Bubser, M, Utley, TJ, Walker, AG, Byun, NE, Lebois, EP, Xiang, Z, Sheffler, DJ, Cho, HP, Davis, AA, Nemirovsky, NE, Mennenga, SE, Camp, BW, Bimonte-Nelson, H, Bode, J, Italiano, K, Morrison, R, Scott Daniels, J, Niswender, CM, Olive, M, Lindsley, CW, Jones, CK & Jeffrey Conn, P 2012, 'Novel allosteric agonists of M 1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models', Journal of Neuroscience, vol. 32, no. 25, pp. 8532-8544. https://doi.org/10.1523/JNEUROSCI.0337-12.2012
Digby, Gregory J. ; Noetzel, Meredith J. ; Bubser, Michael ; Utley, Thomas J. ; Walker, Adam G. ; Byun, Nellie E. ; Lebois, Evan P. ; Xiang, Zixiu ; Sheffler, Douglas J. ; Cho, Hyekyung P. ; Davis, Albert A. ; Nemirovsky, Natali E. ; Mennenga, Sarah E. ; Camp, Bryan W. ; Bimonte-Nelson, Heather ; Bode, Jacob ; Italiano, Kimberly ; Morrison, Ryan ; Scott Daniels, J. ; Niswender, Colleen M. ; Olive, Michael ; Lindsley, Craig W. ; Jones, Carrie K. ; Jeffrey Conn, P. / Novel allosteric agonists of M 1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 25. pp. 8532-8544.
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AU - Lebois, Evan P.

AU - Xiang, Zixiu

AU - Sheffler, Douglas J.

AU - Cho, Hyekyung P.

AU - Davis, Albert A.

AU - Nemirovsky, Natali E.

AU - Mennenga, Sarah E.

AU - Camp, Bryan W.

AU - Bimonte-Nelson, Heather

AU - Bode, Jacob

AU - Italiano, Kimberly

AU - Morrison, Ryan

AU - Scott Daniels, J.

AU - Niswender, Colleen M.

AU - Olive, Michael

AU - Lindsley, Craig W.

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