Relationship between muscarinic M1 receptor binding and cognition in medication-free subjects with psychosis

Abstract

BackgroundIt is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M1 receptor agonists suggest alterations in M1 receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M1 receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M1 receptor binding in relation to cognitive impairments have been done. As cognitive deficits have similar course and prognostic relevance across psychotic disorders, the current study assessed M1 receptor binding in the DLPFC and hippocampus in relation to cognitive functioning.MethodsMuscarinic M1 receptor binding potential (BPND) was measured using 123I-IDEX, single photon emission computed tomography (SPECT) in 30 medication-free subjects diagnosed with a psychotic disorder. A computerized neuropsychological test battery was used to assess cognition, and the positive and negative syndrome scale (PANSS) to assess severity of psychotic symptoms.ResultsAssessment of cognitive domains showed that lower M1 BPND in the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M1 BPND in the DLPFC was related to greater negative symptom severity. Lastly, lower M1 BPND in the hippocampus was related to worse delayed recognition of verbal memory.ConclusionThis is the first study to show that variation in M1 receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M1 receptor may be an important biomarker in biological stratification of patients with psychotic disorders.

Widespread Changes in Positive Allosteric Modulation of the Muscarinic M1 Receptor in Some Participants With Schizophrenia

“…This is important because it is argued such drugs will be a new treatment for schizophrenia (Conn et al, 2009). However, the use of either SPECT (Raedler et al, 2003; Bakker et al, 2018) or PET would be advisable to determine if participants with a marked loss of CHRM1s and schizophrenia had been recruited into drug trials of CHRM1 allosteric modulators to treat the disorder.…”

“…There is a growing body of evidence that includes data from neuroimaging, postmortem CNS, and preclinical pharmacology suggesting that there is a role for the muscarinic M1 receptor (CHRM1) in the pathophysiology and treatment of schizophrenia (Raedler et al, 2007; Gibbons and Dean, 2016). Center to this hypothesis was evidence to suggest there were lower levels of CHRM1s in many CNS regions in participants with the disorder (Raedler et al, 2003) and that levels of CHRM1 in the dorsolateral prefrontal cortex were inversely related to cognitive ability and correlated with the severity of negative symptoms (Bakker et al, 2018). Notably, soon after the demonstration of lower levels of CHRM1 in the CNS from participants with schizophrenia, it was suggested that activating the CHRM1 could prove to have therapeutic benefits for those with the disorder (Felder et al, 2001; Dean et al, 2003).…”

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

“…In schizophrenia, altered cholinergic neurotransmission is intimately linked to the defective cognitive functions associated primarily with cortical and hippocampal regions. Post-mortem studies consistently reported transcriptional and proteomic alterations in M 1 and M 4 receptors in the hippocampus [ 112 , 113 ] prefrontal and frontal cortices [ 112 , 114 , 115 , 116 ], and also cingulate cortex [ 117 , 118 ] of schizophrenic patients. Conversely, potentiation of the central muscarinic system by M 1 mAChR’s positive allosteric modulator (PAM), completely restored defective long-term depression as well as impairments in the cognitive function and social interaction in PCP-treated mouse model of schizophrenia [ 119 ].…”

MATLAB doesn't love me: an essay

“…NEUROSCIENTISTS DO Figure 1 shows a simplified example of a magnetic resonance spectroscopy (MRS) work flow commonly used to examine neurochemical mechanisms and drug efficacy in neuropsychiatric and neurological disorders (e.g., [2,11]). Dealing with multi-vendor data is common due to use of historical data, multi-site scanning, consortium data, vendor switching within hospitals, research dedicated versus clinical scanners, PET-MRI combined machines, and level of investment from vendors to advance new sequences.…”