Sleep and mental disorders: role of Acetylcholine muscarinic receptors in pathophysiology and their therapeutic potential
Main Article Content
Abstract
Sleep is a neurophysiological state characterized by a gradual decrease in consciousness and alertness in organisms. It is essential for the optimal development of human and other animal species.
In turn, Acetylcholine participates as a neuromodulator for sleep regulation, synaptic transmission and neuronal plasticity through the activation of muscarinic Acetylcholine receptors. Furthermore, sleep disturbances are a common feature across a wide range of mental disorders, including schizophrenia, depression and substance abuse.
Increasing evidence suggests that the cholinergic system, particularly muscarinic Acetylcholine receptors, plays a central role in regulating sleep architecture, cognition, and emotional processes. This review examines the participation of muscarinic Acetylcholine receptors (M1–M5) in the regulation of sleep and in the pathophysiology of mental disorders, and evaluates their potential as therapeutic targets. Current findings indicate that these receptors are differentially involved in modulating cognitive, emotional, and behavioral functions. In particular, the muscarinic Acetylcholine receptors M1 and M4 subtypes are closely associated with sleep and dopaminergic regulation and have demonstrated therapeutic potential in conditions such as schizophrenia and substance use disorders. The muscarinic Acetylcholine receptor-M2 appears to be involved in the generation of REM sleep and affective regulation in depressive states, while muscarinic Acetylcholine receptors-M3 and M5 contribute more indirectly to neural modulation and system-wide balance. Across disorders, alterations in muscarinic signaling are consistently linked to disruptions in sleep architecture, synaptic plasticity, and neural network stability. Overall, muscarinic Acetylcholine receptors represent a promising target for the development of more precise and integrative therapeutic strategies in psychiatry. However, further research is needed to improve pharmacological selectivity and to clarify their clinical applicability.
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References
2. Aakash K. Patel, Reddy, V., Shumway, K. R., & Araujo, J. F. Physiology, Sleep Stages. J Sleep Sci. 2024:45(2), 115–128.
3. Rosales-Lagarde A, Díaz JL, Muller M, Jiménez Anguiano A, eds. La naturaleza de los sueños. Cerebro, mente y cultura. 1ª ed. Ciudad de México: Herder-UAM, 2018: 85-221.
4. Yamada R, Ueda H. Molecular mechanisms of REM sleep. Front Neurosci. 2020; 13: 1402-15.
5. Drucker-Colín R, Arankowsky-Sandoval G, Prospéro-García O, Jiménez-Anguiano A, Merchant H. In: The diencephalon and sleep. Mancia M, ed. The regulation of REM sleep: some considerations on the role of vasoactive intestinal peptide, acetylcholine and sensory modalities. 1th ed. New York, USA: Raven Press, 1990: 313-30.
6. Haam J, Yakel J. Cholinergic modulation of the hippocampal region and memory function. J Neurochem. 2017; 142: 111-21.
7. López-Villa JE. Los receptores muscarínicos como potencial objetivo terapéutico en la esquizofrenia. Eneurobiología. 2024;15(38).
8. Vaidya S, Guerin AA, Walker LC, Lawrence AJ. Clinical effectiveness of muscarinic receptor-targeted interventions in neuropsychiatric disorders: A systematic review. CNS Drugs. 2022; 36:1171-1206.
9. Yousef O, Abouelmagd ME, Khaddam H, Shbani A, Yousef R, Meshref M, et al. The effectiveness of melatonin for sleep disturbances in Parkinson’s disease: Systematic review and meta-analysis. J Sleep Res. 2025;35: e70097. doi:10.1111/jsr.70097
10. Younes M, Gerardy B, Pack AI, Kuna ST, Castro-Diehl C, Redline S. Sleep architecture based on sleep depth and propensity: patterns in different demographics and sleep disorders and association with health outcomes. Sleep 2022; 45: 1-15.
11. Rogers K. Acetylcholine. Encyclopedia Britannica [ online version]. NewYork, EU. 2020.
12. Vilaro MT, Palacios JM. and Mengod G. Multiplicity of muscarinic autoreceptor subtypes? Comparison of the distribution of cholinergic cells and cells containing mRNA for five subtypes of muscarinic receptors in the rat brain. Mol Brain Res. 1994; 21: 30–46.
13. Dean B, Bakker G, Ueda HR, Tobin AB, Brown A, Kanaan RAA. A growing understanding of the role of muscarinic receptors in the molecular pathology and treatment of schizophrenia. Front Cell Neurosci. 2023; 17:1124333.
14. Monaco M, Trebesova H, Grilli M. Muscarinic receptors and Alzheimer’s disease: New perspectives and mechanisms. Curr Issues Mol Biol. 2024; 46:6820-35.
15. Hernández-Peón R. Central neuro-humoral transmission in sleep and wakefulness. Prog Brain Res. 1965; 18:96-117.
16. Datta S. and Hobson A. Neuronal activity in the caudo-lateral peribrachial pons: relationship to PGO waves and rapid eyes movements. J Neurophysiol.1994;71: 95-109.
17. Datta S. and Siwek D. Excitation of the brain stem pedunculopontine tegmentum cholinergic cells induce wakefulness and REM sleep. J. Neurophysiol. 1997; 77: 2975- 2988.
18. Webster J. and Jones B. 1988. Neurotoxic lesions of the dorsolateral pontomesencephalic-tegmentum-cholinergic cell area in the cat. Effects upon sleep-waking states. Brain Res. 1988;458: 285-302.
19. Lydic R. and Baghdoyan H. Pedunculopontine stimulation alters respiration and increases ACh release in the pontine reticular formation. Am J Physiol. 1999;193;264: R544-54.
20. Feld G, Born J. Neurochemical mechanisms for memory processing during sleep: basic findings in humans and neuropsychiatric implications. Neuropsychopharmacol. 2019; 45: 31–44.
21. Ramírez-Salado I, Rivera-García AP, Velázquez-Moctezuma J, Jiménez-Anguiano A, Pellicer F. GABA-A receptor agonist at the caudo-lateral peribrachial area suppresses ponto-geniculo-occipital waves and its related states. Pharmacol, Biochem Behav. 2014; 124: 333–40.
22. Gillin JC, Salin-Pascual R, Velazquez-Moctezuma J, Shiromani P. and Zoltoski, R. Cholinergic receptor subtypes and REM sleep in animals and normal controls. Prog Brain Res. 1993; 98:379-87.
23. Velázquez-Moctezuma J, Jiménez-Anguiano A. and Vázquez-Palacios G. Participación de los subtipos de receptores colinérgicos en la regulación del sueño MOR. Vigilia-Sueño. 1998;10: 46-53.
24. Baghdoyan H. and Lydic R. M2 muscarinic receptor subtype in the feline medial pontine reticular formation modulates the amount of rapid eye movement sleep. Sleep. 1999; 22(7):835-47.
25. Chen J, Liu Y, Su M, Sun Y, Liu C, Sun S, et al. The aggregation of α-synuclein in the dorsomedial striatum significantly impairs cognitive flexibility in Parkinson’s disease mice. Biomedicines. 2024;12(8):1634-38.
26. Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, et al. Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A. 2008;105(31):10978-983.
27. Moehle MS, Bender AM, Dickerson JW, Foster DJ, Qi A, Cho HP, et al. Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo antiparkinsonian and antidystonic efficacy. ACS Pharmacol Transl Sci. 2021;4(4):1306-21.
28. Cadeddu R, Braccagni G, Branca C, van Luik ER, Pittenger C, Thomsen MS, et al. Activation of M4 muscarinic receptors in the striatum reduces tic-like behaviours in two distinct murine models of Tourette syndrome. Br J Pharmacol. 2024;181(17):3064-81.
29. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5): e141.
30. Schultz SH, North SW, Shields CG. Schizophrenia: a review. Am Fam Physician. 2007; 15;75(12):1821-29.
31. Cohrs S. Sleep disturbances in schizophrenia: Current perspectives. Nat Sci Sleep. 2022; 14:237-249.
32. Wulff K, Dijk DJ, Middleton B, Foster RG, Joyce EM. Sleep and circadian rhythm disruption in schizophrenia. Br J Psychiatry. 2023;222(3):108-16.
33. Ferrarelli F, Tononi G. Reduced sleep spindles in schizophrenia: A marker of thalamocortical dysfunction. Biol Psychiatry. 2022;92(1):12-21.
34. Reeve S, Sheaves B, Freeman D. Sleep dysfunction and psychosis risk: A systematic review and meta-analysis. Schizophr Bull. 2023;49(2):412-23.
35. Waite F, Sheaves B, Isham L, Reeve S, Freeman D. Treating sleep problems in schizophrenia: A randomized controlled trial of cognitive behavioural therapy for insomnia. Lancet Psychiatry. 2022;9(5):404-14.
36. Siafis S, Nomura N, Schneider-Thoma J, Bighelli I, Bannach-Brown A, Ramage FJ, et al. Muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis: Protocol for a systematic review and meta-analysis. F1000Res. 2025; 13:1017.
37. Guo X, Deng R, Lai J, Hu S. Is muscarinic receptor agonist effective and tolerant for schizophrenia? BMC Psychiatry. 2025; 25:323.
38. Pejčić AV. Targeting muscarinic receptors in schizophrenia treatment: Novel antipsychotic xanomeline/ trospium chloride. World J Psychiatry. 2025;15(6):105409.
39. Paul SM, Yohn SE. Targeting muscarinic receptors for treating schizophrenia. Neurotherapeutics. 2026;23(1): e00839.
40. Cadeddu R, Braccagni G, Branca C, van Luik ER, Pittenger C, Thomsen MS, et al. Activation of M4 muscarinic receptors in the striatum reduces tic-like behaviours in two distinct murine models of Tourette syndrome. Br J Pharmacol. 2024;181(17):3064-81.
41. Tsimpili H. A new era of muscarinic acetylcholine receptor modulators in neuropsychiatric disorders. Front Neurosci. 2025.
42. Güleç A, Katipoglu B. Beyond symptom control: The unseen effects of anticholinergic burden on executive functions and sleep quality in adolescents with depression. Prog Neuropsychopharmacol Biol Psychiatry. 2026; 146:111658.
43. Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Duman RS. Role of M2 muscarinic acetylcholine receptors in rapid antidepressant response. Proc Natl Acad Sci U S A. 2021;118(32): e2108361118.