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Review
. 2021 May 7:405:113201.
doi: 10.1016/j.bbr.2021.113201. Epub 2021 Feb 26.

Targeting muscarinic receptors to treat schizophrenia

Daniel J Foster  1 , Zoey K Bryant  1 , P Jeffrey Conn  2
Affiliations
Review

Targeting muscarinic receptors to treat schizophrenia

Daniel J Foster et al. Behav Brain Res. .

Abstract

Schizophrenia is a severe neuropsychiatric disorder characterized by a diverse range of symptoms that can have profound impacts on the lives of patients. Currently available antipsychotics target dopamine receptors, and while they are useful for ameliorating the positive symptoms of the disorder, this approach often does not significantly improve negative and cognitive symptoms. Excitingly, preclinical and clinical research suggests that targeting specific muscarinic acetylcholine receptor subtypes could provide more comprehensive symptomatic relief with the potential to ameliorate numerous symptom domains. Mechanistic studies reveal that M1, M4, and M5 receptor subtypes can modulate the specific brain circuits and physiology that are disrupted in schizophrenia and are thought to underlie positive, negative, and cognitive symptoms. Novel therapeutic strategies for targeting these receptors are now advancing in clinical and preclinical development and expand upon the promise of these new treatment strategies to potentially provide more comprehensive relief than currently available antipsychotics.

Keywords: Acetylcholine; Dopamine; Muscarinic; Schizophrenia.

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Figures

Figure 1:
Figure 1:. Muscarinic receptor based therapies have the potential to provide more comprehensive relief to schizophrenia patients than currently available dopamine receptor-based approaches.
Positive allosteric modulators (PAMs) targeting M4 and M1 receptor subtypes can mediate pro-cognitive and antipsychotic-like activity in preclinical animal models, while M5-selective negative allosteric modulators (NAMs) have potential in treating antihedonic and depressive symptoms. Collectively, targeting muscarinic receptors has the potential to alleviate all three symptom clusters in schizophrenia patients including cognitive and negative symptom clusters that are currently not alleviated by currently used antipsychotics.
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