ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2013
The muscarinic acetylcholine receptor agonist BuTAC mediates antipsychotic-like effects via the M4 subtype.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- Novel drug treatments for schizophrenia.Nature reviews. Drug discovery · 2026Review
- Downstream Signaling of Muscarinic MPharmacology research & perspectives · 2025Article
- The mechanism of action of clozapine.Journal of psychopharmacology (Oxford, England) · 2025Article
- The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- MMolecular and cellular endocrinology · 2018Article
- Physiological roles of CNS muscarinic receptors gained from knockout mice.Neuropharmacology · 2018Review
- Positive allosteric modulation of MNeuropharmacology · 2018Review
- A Guide to Single-Cell Transcriptomics in Adult Rodent Brain: The Medium Spiny Neuron Transcriptome Revisited.Frontiers in cellular neuroscience · 2018Article
- Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates.PloS one · 2015Article
- HDAC inhibitors restore the capacity of aged mice to respond to haloperidol through modulation of histone acetylation.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Article
- Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia.Neuropsychiatric disease and treatment · 2014Review
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Authors and funding
8 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The generation of muscarinic acetylcholine receptor (mAChR) subtype-selective compounds has been challenging, requiring use of nonpharmacological approaches, such as genetically engineered animals, to deepen our understanding of the potential that members of the muscarinic receptor subtype family hold as therapeutic drug targets. The muscarinic receptor agonist 'BuTAC' was previously shown to exhibit efficacy in animal models of psychosis, although the particular receptor subtype(s) responsible for such activity was unclear. Here, we evaluate the in vitro functional agonist and antagonist activity of BuTAC using an assay that provides a direct measure of G protein activation. In addition, we employ the conditioned avoidance response paradigm, an in vivo model predictive of antipsychotic activity, and mouse genetic deletion models to investigate which presynaptic mAChR subtype mediates the antipsychotic-like effects of BuTAC. Our results show that, in vitro, BuTAC acts as a full agonist at the M2AChR and a partial agonist at the M1 and M4 receptors, with full antagonist activity at M3- and M5AChRs. In the mouse conditioned avoidance response (CAR) assay, BuTAC exhibits an atypical antipsychotic-like profile by selectively decreasing avoidance responses at doses that do not induce escape failures. CAR results using M2(-/-), M4(-/-), and M2/M4 (M2/M4(-/-)) mice found that the effects of BuTAC were near completely lost in M2/M4(-/-) double-knockout mice and potency of BuTAC was right-shifted in M4(-/-) as compared with wild-type and M2(-/-) mice. The M2/M4(-/-) mice showed no altered sensitivity to the antipsychotic effects of either haloperidol or clozapine, suggesting that these compounds mediate their actions in CAR via a non-mAChR-mediated mechanism. These data support a role for the M4AChR subtype in mediating the antipsychotic-like activity of BuTAC and implicate M4AChR agonism as a potential novel therapeutic mechanism for ameliorating symptoms associated with schizophrenia.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.