Possible Involvement of Muscarinic Receptors in Psychiatric Disorders: A Focus on Schizophrenia and Mood Disorders
Abstract
A considerable body of data supports a role for the central cholinergic system in the aetiologies of schizophrenia and mood disorders. There have been breakthroughs in gaining structural data on muscarinic receptors (CHRMs), understanding their role in CNS functioning and in synthesising drugs that can specifically target each of the 5 CHRMs. This means it is opportune to consider the role of specific CHRMs in the pathophysiologies of schizophrenia and mood disorders. This review will focus on data suggesting changes in levels of CHRM1 and CHRM4 implicate these receptors in the pathophysiology of schizophrenia whereas data suggest a role for CHRM2 in mood disorders. There will be a selected reference to recent developments in understanding the roles of CHRM1, 2 and 4 in CNS function and how these predict mechanisms by which these receptors could induce the symptoms prevalent in schizophrenia and mood disorders. Finally, there will be comments on the potential advantages and problems in targeting CHRM1 and CHRM4 to treat the symptoms of schizophrenia and CHRM2 to treat the symptom of depression.
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Several lines of evidence indicate that supersensitivity of the muscarinic cholinergic system is implicated in the pathophysiology of major depressive disorder.
“Several lines of evidence indicate that supersensitivity of the muscarinic cholinergic system is implicated in the pathophysiology of MDD [152].”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [152]
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Cognitive remission: a novel objective for the treatment of major depression?
Bortolato, B., Miskowiak, K. W., Köhler, C. A., Maes, M., Fernandes, B. S., Berk, M., & Carvalho, A. F. (2016) · BMC Medicine · doi:10.1186/s12916-016-0560-3 · Cited by 252 · see citing works
“of the muscarinic cholinergic system is implicated in the pathophysiology of MDD [152].”
BackgroundG protein-coupled receptors in neurodegenerative diseases and psychiatric disorders
Wong, T., Li, G., Li, S., Gao, W., Chen, G., Gan, S., Zhang, M., Li, H., Wu, S., & Du, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01427-2 · Cited by 168 · see citing works
“M4 receptor promotes the development of the dopamine hypersensitivity phenotype of schizophrenia.(133) It has G protein-coupled receptors in neurodegenerative diseases and psychiatric.”
BackgroundMuscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia
Paul, S. M., Yohn, S. E., Popiolek, M., Miller, A., & Felder, C. C. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.21101083 · Cited by 149 · see citing works
Multi-Target Approach for Drug Discovery against Schizophrenia
Kondej, M., Stępnicki, P., & Kaczor, A. A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103105 · Cited by 103 · see citing works
“A growing body of evidence indicates central role of disturbances in cholinergic neurotransmission in schizophrenia [44].”
BackgroundAltered brain arginine metabolism in schizophrenia
Liu, X., Yu, J., Collie, N. D., Dean, B., Bilkey, D. K., & Zhang, H. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.144 · Cited by 72 · see citing works
Self-citationScarr, E., Hopper, S., Vos, V., Seo, M. S., Everall, I., Aumann, T. D., Chana, G., & Dean, B. (2018) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.170202 · Cited by 45 · see citing works
Self-citationYu, H., Li, M., Zhou, D., Lv, D., Liao, Q., Lou, Z., Shen, M., Wang, Z., Li, M., Xiao, X., et al. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.12.028 · Cited by 40 · see citing works
“Over the past decade, accumulating evidence has reported a positive relationship between depression and the cholinergic system (Janowsky et al., 1972; Risch et al., 1981; Drevets et al., 2013; Jeon et al., 2015; Papakostas and Ionescu, 2015; Dean and Scarr, 2015), with the underlying hypothesis being that hypersensiti…”
BackgroundGenetic and neuroendocrine regulation of the postpartum brain
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“Chrm4 has been linked to psychiatric disorders (Dean and Scarr, 2015) and is coexpressed with Pdyn in neurons (Heiman et al.”
BackgroundHoriuchi, Y., Kondo, M., Okada, K., Takayanagi, Y., Tanaka, T., Ho, T., Varvaris, M., Tajinda, K., Hiyama, H., Ni, K., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.154 · Cited by 34 · see citing works
Udawela, M., Scarr, E., Boer, S., et al. (2017) · Schizophrenia · doi:10.1038/s41537-017-0020-x · Cited by 27 · see citing works
“Interestingly, Plcb1 mice show reduced radioligand binding to CHRM1/4 in the cortex and hippocampus,(16) again aligning with findings in subjects with Sz of decreased binding to and expression of these receptors in the same CNS regions.(18) This interactive regulation between muscarinic receptors and PLCB1 displayed i…”
BackgroundSelf-citationIn Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia
Koszła, O., Targowska‐Duda, K. M., Kędzierska, E., & Kaczor, A. A. (2020) · Biomolecules · doi:10.3390/biom10010160 · Cited by 26 · see citing works
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“Collectively, these data provide considerable support for region-specific differences in M2 or M3 receptors in patients with mood disorders, but no apparent regulation of M1 receptor [28, 29].”
ResultDean, B., Copolov, D., & Scarr, E. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2016.04.037 · Cited by 14 · see citing works
Self-citationWakeham, M. C. L., Davie, B. J., Chalmers, D. K., Christopoulos, A., Capuano, B., Valant, C., & Scammells, P. J. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00572 · Cited by 9 · see citing works
Doostparast Torshizi, A., Duan, J., & Wang, K. (2020) · Patterns · doi:10.1016/j.patter.2020.100091 · Cited by 5 · see citing works
Ma, Y., Wang, C., Shi, M., et al. (2022) · Molecular and Clinical Oncology · doi:10.3892/mco.2022.2582 · Cited by 4 · see citing works
“Several studies have revealed that CHRM2 is associated with the pathophysiology of schizophrenia (75).”
EDITORIAL (Thematic Issue: New Targets of Medical Treatment in Psychiatric Disorders)
Yui, K. (2015) · Current Neuropharmacology · doi:10.2174/1570159x1306151126144423
“The finding on the association between decreased CHRM3 receptor expression and bipolar disorder suggests that bipolar and major depressive disorder differs in the underlying mechanism of dysfunction of cholinergic systems [5].”
BackgroundMerino, P. (2019) · doi:10.1002/9783527813421.ch4 · Cited by 1 · see citing works
Lao, Y., Zhang, W., Li, X., He, L., Bai, Y., Li, X., Guan, X., Wang, W., & Dong, Z. (2022) · Research Square · doi:10.21203/rs.3.rs-1840553/v1
- Authors
- Dean, B., & Scarr, E.
- Affiliations
- Florey Institute of Neuroscience and Mental Health (AU)
- Venue
- Current Molecular Medicine
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2015-05-04
- Volume
- 15
- Issue
- 3
- Pages
- 253-264
- ISSN
- 1566-5240 (ISSN-L)
- OpenAlex
- W241778565
- Cited by
- 19
- References
- 0
- Citations by year
- 2023: 1 · 2022: 4 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 1
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- muscarinic receptors, schizophrenia, mood disorders, depression, cholinergic system, M1 muscarinic receptor, M2 muscarinic receptor, receptor subtypes, pathophysiology, antipsychotic drug targets, muscarinic agonists
- MeSH terms
- Animals, Brain, Depression, Humans, Synaptic Transmission, Receptors, Muscarinic, Schizophrenia, Mood Disorders
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