ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2021
The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 2 of them syntheses that pooled it.
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Who cites it
31 citing papers in PubMed, 2 syntheses or guidelines pooled it, 55 citations in OpenAlex.
- Impact of selected second and third generation antipsychotics on cognitive dysfunction in schizophrenia-spectrum disorders. Systematic review and network meta-analysis.International clinical psychopharmacology · 2026Pooled it
- Is muscarinic receptor agonist effective and tolerant for schizophrenia?BMC psychiatry · 2025Pooled it
- Xanomeline-trospium reverses phencyclidine-induced cognitive deficits through modulation of the gut microbiota-brain axis in mice.Translational psychiatry · 2026Article
- Connectomic and behavioural alterations in creatine transporter deficiency are partially normalized by gene therapy.Brain : a journal of neurology · 2026Article
- Beyond dopamine: KarXT and emerging mechanism-based therapies in schizophrenia.Frontiers in psychiatry · 2026Review
- Targeting muscarinic receptors for treating schizophrenia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Xanomeline-trospium: defining its place among the current antipsychotic landscape.Acta neuropsychiatrica · 2025Review
- A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Negative Symptoms in Schizophrenia: An Update on Research Assessment and the Current and Upcoming Treatment Landscape.CNS drugs · 2025Review
- Distinct Effects of Olanzapine Depot Treatment on Behavior and Muscarinic M1 Receptor Expression in the Triple-Hit Wisket Rat Model of Schizophrenia.Genes, brain, and behavior · 2025Article
- Corticolimbic circuitry as a druggable target in schizophrenia spectrum disorders: a narrative review.Translational psychiatry · 2025Review
- The excitatory-inhibitory balance as a target for the development of novel drugs to treat schizophrenia.Biochemical pharmacology · 2024Review
- Activation of MBritish journal of pharmacology · 2024Article
- Neurochemical organization of cortical proteinopathy and neurophysiology along the Alzheimer's disease continuum.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Clinical utility of fMRI in evaluating of LSD effect on pain-related brain networks in healthy subjects.Heliyon · 2024Article
- Sex-biasing influence of autism-associatedScience advances · 2024Article
- Alignments between cortical neurochemical systems, proteinopathy and neurophysiological alterations along the Alzheimer's disease continuum.medRxiv : the preprint server for health sciences · 2024Article
- Serine racemase deletion alters adolescent social behavior and whole-brain cFos activation.Frontiers in psychiatry · 2024Article
- Connecting dots of long COVID-19 pathogenesis: a vagus nerve- hypothalamic-pituitary- adrenal-mitochondrial axis dysfunction.Frontiers in cellular and infection microbiology · 2024Review
- New Developments in the Treatment of Schizophrenia: An Expert Roundtable.The international journal of neuropsychopharmacology · 2023Article
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Authors and funding
14 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances, or psychosis, such as Alzheimer's disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI), and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally active dose of the M1/M4-preferring muscarinic agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high-frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high-frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.
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