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.

• Authors: Shaun Hopper, Geoffrey Mark Pavey, Andrea Gogos, Brian Dean
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 22 Issue 10 Pg. 640-650 (10 01 2019) ISSN: 1469-5111 [Electronic] England
• PMID: 31428788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of CINP.

Chemical References

• CHRM1 protein, human
• Quinolones
• Receptor, Muscarinic M1
• Tritium
• N-Methylscopolamine

Topics

• Allosteric Regulation
• Autoradiography
• Case-Control Studies
• Cerebral Cortex (metabolism)
• Corpus Striatum (metabolism)
• Female
• Hippocampus (metabolism)
• Humans
• Male
• Middle Aged
• N-Methylscopolamine (metabolism)
• Protein Binding (drug effects)
• Quinolones (metabolism)
• Radioligand Assay (methods)
• Receptor, Muscarinic M1 (agonists, deficiency)
• Schizophrenia (metabolism)
• Tritium (metabolism)