Widespread Changes in Positive Allosteric Modulation of the Muscarinic M1 Receptor in Some Participants With Schizophrenia.
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
Schizophrenia
/ metabolism
Tritium
/ metabolism
hippocampus
musccarinic M1 receptor
positive allosteric modulation
schizophrenia
striatum
Journal
The international journal of neuropsychopharmacology
ISSN: 1469-5111
Titre abrégé: Int J Neuropsychopharmacol
Pays: England
ID NLM: 9815893
Informations de publication
Date de publication:
01 10 2019
01 10 2019
Historique:
received:
24
06
2019
revised:
22
07
2019
accepted:
15
08
2019
pubmed:
21
8
2019
medline:
20
5
2020
entrez:
21
8
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31428788
pii: 5552010
doi: 10.1093/ijnp/pyz045
pmc: PMC6822142
doi:
Substances chimiques
CHRM1 protein, human
0
Quinolones
0
Receptor, Muscarinic M1
0
Tritium
10028-17-8
N-Methylscopolamine
VDR09VTQ8U
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
640-650Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.
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