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.

Keywords: hippocampus; musccarinic M1 receptor; positive allosteric modulation; schizophrenia; striatum.

© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.

Method optimization utilizing tissue from Brodmann’s area (BA) 6. (A) The binding of [3H]NMS (0.4 nM) (mean ± SEM) to frozen sections from 3 cases in the presence of increasing concentrations of acetylcholine. (B) The binding of [3H]NMS (0.4 nM) (mean ±SEM) to frozen sections from 3 cases in the presence of a standard concentration of acetylcholine and in the absence or presence of 3 µM benzyl quinolone carboxylic acid (BQCA). Example autoradiographs are included for each binding condition. (C) BQCA-mediated binding (mean ± SEM) measured as the difference between [3H]n-methyl scopolamine ([3H]NMS: 0.4 nM) binding to particulate membrane from 5 cases in the presence of a standard dose of acetylcholine (1 nM) and in the presence or absence of 3µM BQCA.

Figure 2.

The specific binding of [3H]n-methyl scopolamine ([3H]NMS; A and B) and benzyl quinolone carboxylic acid (BQCA)-mediated [3H]NMS binding (C and D) in Brodmann’s area 6 (A and C) and the striatum (B and D) from participants with schizophrenia, sex-matched controls, muscarinic receptor deficit schizophrenia (MRDS) and participants with schizophrenia and no marked deficits in cortical muscarinic receptors (non-MRDS). Mean and SEM shown for each measure. ETE, estimated tissue equivalents.

Figure 3.

The specific binding of [3H]n-methyl scopolamine ([3H]NMS) to the hippocampus of participants with schizophrenia, controls, muscarinic receptor deficit schizophrenia (MRDS) and participants with schizophrenia and no marked deficits in cortical muscarinic receptors (non-MRDS). Mean and SEM shown for each measure. CA, cornu ammonis; a-p, alveus to pyramidal layers; lm/r, lacunosum moleculare and stratum radiatum; M/G DG, molecular and granular layers of the dentate gyrus; ML, molecular layer; Poly DG, polymorphic layer of the dentate gyrus; p/p, polymorphic and pyramidal layers.

Figure 4.

Benzyl quinolone carboxylic acid (BQCA)-mediated binding to the hippocampus from participants with schizophrenia, controls, muscarinic receptor deficit schizophrenia (MRDS) and participants with schizophrenia and no marked deficits in cortical muscarinic receptors (non-MRDS). Mean and SEM shown for each measure. a-p, alveus to pyramidal layers; CA, cornu ammonis; lm/r, lacunosum moleculare and stratum radiatum; M/G DG, molecular and granular layers of the dentate gyrus; ML, molecular layer; Poly DG, polymorphic layer of the dentate gyrus; p/p, polymorphic and pyramidal layers.