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

Abstract

Background Preclinical and some human data suggest allosteric modulation of the muscarinic M1 receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a subgroup of participants with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some participants with schizophrenia may not respond optimally to CHRM1 allosteric modulation. Here we describe a novel methodology to measure positive allosteric modulation of CHRM1 in human CNS and the measurement of that response in the cortex, hippocampus, and striatum from participants with MRDS, non-MRDS and controls. Methods The cortex (Brodmann’s area 6), hippocampus, and striatum from 40 participants with schizophrenia (20 MRDS and 20 non-MRDS) and 20 controls were used to measure benzyl quinolone carboxylic acid-mediated shift in acetylcholine displacement of [3H]N-methylscopolamine using a novel in situ radioligand binding with autoradiography methodology. Results Compared with controls, participants with schizophrenia had lower levels of specific [3H]N-methylscopolamine binding in all CNS regions, whilst benzyl quinolone carboxylic acid-modulated binding was less in the striatum, Brodmann’s area 6, dentate gyrus, and subiculum. When divided by subgroup, only in MRDS was there lower specific [3H]N-methylscopolamine binding and less benzyl quinolone carboxylic acid-modulated binding in all cortical and subcortical regions studied. Conclusions In a subgroup of participants with schizophrenia, there is a widespread decreased responsiveness to a positive allosteric modulator at the CHRM1. This finding may have ramifications it positive allosteric modulators of the CHRM1 are used in clinical trials to treat schizophrenia as some participants may not have an optimal response.

Higher levels of α7 nicotinic receptors, but not choline acetyltransferase, in the dorsolateral prefrontal cortex from a sub-group of patients with schizophrenia

“…xanomeline and the peripheral muscarinic receptor antagonist, trospium, does reduce the symptoms of the disorder (for review see (Dean and Scarr, In Press)). However, there is some data using CHRM1 orthosteric (Salah-Uddin et al, 2009) and allosteric agonists (Dean et al, 2016;Hopper et al, 2019) to activate that receptor in human cortex, that suggests patients with MRDS may not respond optimally to such treatments. It is therefore intriguing to postulate whether treating patients with MRDS with CHRNA7 antagonists to reduce the increased signalling through the high levels of that receptor could have therapeutic benefits for MRDS.…”

Current Advances in Allosteric Modulation of Muscarinic Receptors

“…However, cortex, hippocampus, and striatum post mortem samples from some patients with schizophrenia have shown a profound loss of muscarinic receptors and decreased responsiveness to M 1 -selective PAM of acetylcholine BQCA. These findings may explain why some individuals with schizophrenia may not respond to such [84].…”

Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias

“…This finding is important, because treatment of this subset of schizophrenic patients with M 1 mAChR-selective ligands may fail. Indeed, in [ 3 H]-N-methyl-scopolamine binding experiments using post-mortem brain tissues from MRDS and nonschizophrenics, an M 1 mAChR-selective ligand, benzyl quinolone carboxylic acid (BQCA), had much weaker effects in the MRDS tissues than in the non-schizophrenic control tissues (Dean et al, 2016;Hopper et al, 2019). Thus, targeting an alternative receptor, such as the M 4 mAChR, may be more beneficial for this subgroup of schizophrenic patients.…”