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Development

The Role of M1 Signaling in Cognitive and Behavioral Symptoms of Psychosis

By Dr Geor Bakker | Mar 9, 2021

Summary

Dr Geor Bakker, Senior Scientist Neuro in the Sosei Heptares Experimental Medicine team, was invited to speak at the 2021 International College of Neuropsychopharmacology (CINP) Virtual World Conference by Prof Brian Dean (Florey Institute) to talk about the relationship between muscarinic M1 receptor expression and psychotic symptom severity and cognitive deficits in patients in the early phase of a psychotic disorder, including patients diagnosed with schizophrenia. Data presented are the first to show an association between lower M1 receptor binding in the dorsolateral prefrontal cortex and greater deficits in learning and memory  processes and negative symptom severity. Also indications of loss of M1 receptor reserve in limbic areas compared to matched controls were found.

About the Conference

International College of Neuropsychopharmacology (CINP) Virtual World Conference 2021

26-28 February 2021

Conference Website Link

Dr Geor Bakker presented in the Symposium focused on “The Importance of the Muscarinic M1 Receptor in CNS Function and as a Drug Target”. She was joined by the following speakers:

  • Brian Dean (Australia) – “Evidence suggesting the Muscarinic M1 Receptor has a role in the Aetiology and Treatment of Schizophrenia”
  • Hiroki Ueda (Japan) – “Systems Biology of Mammalian Sleep/Wake Cycles: The roles of Muscarinic Acetylcholine Receptor in NREM and REM Sleep”
  • Andrew Tobin (United Kingdom) – “The Muscarinic M1 Receptor in CNS Function and as a Drug Target for slowing the progression of Neurodegenerative Disease”

Abstract

There are longstanding implications that cognitive deficits in psychosis are related to loss of muscarinic M1 receptor (M1R) functioning. Post-mortem data has shown reductions in M1R expression in critical areas for cognition and in patients with schizophrenia pro-cognitive effects were seen after administration of M1/4 agonist xanomeline. A study using non-selective M1/4 radiotracer IQNB also showed reduced M1 and M4 receptor availability in patients with schizophrenia compared to controls. These studies however were done in chronic patients and confounded by use of antipsychotic medication. Since these studies, we have shown that SPECT radiotracer I-IDEX is more selective for the M1R over M4 receptor. We used this tracer to investigate how M1R binding relates to cognitive functioning in medication free patients with a psychotic disorder (PsychDis). In addition, functional MRI with M1 selective antagonist biperiden was used to assess differences in M1 mediated functional response underlying associative learning and memory between patients and controls. Results from these studies showed that lower M1 binding in the dorsolateral-prefrontal cortex was predictive of worse verbal learning and memory and greater negative symptom severity. Patients with PsychDis also showed significantly greater hyperactivation of limbic areas during associative learning and memory compared to controls after administration of biperiden. This finding suggests loss of M1R reserve in PsychDis modulating glutamate involved long term potentiation in limbic regions. These data support loss of M1 mediated signalling in early phases of the disorder, and drugs targeting the M1R may be promising treatment strategy for cognitive and negative symptoms.

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