Journal article

Changes in BQCA Allosteric Modulation of [H-3]NMS Binding to Human Cortex within Schizophrenia and by Divalent Cations

Brian Dean, Shaun Hopper, P Jeffrey Conn, Elizabeth Scarr

NEUROPSYCHOPHARMACOLOGY | NATURE PUBLISHING GROUP | Published : 2016

Abstract

Stimulation of the cortical muscarinic M1 receptor (CHRM1) is proposed as a treatment for schizophrenia, a hypothesis testable using CHRM1 allosteric modulators. Allosteric modulators have been shown to change the activity of CHRMs using cloned human CHRMs and CHRM knockout mice but not human CNS, a prerequisite for them working in humans. Here we show in vitro that BQCA, a positive allosteric CHRM1 modulator, brings about the expected change in affinity of the CHRM1 orthosteric site for acetylcholine in human cortex. Moreover, this effect of BQCA is reduced in the cortex of a subset of subjects with schizophrenia, separated into a discrete population because of a profound loss of cortical [..

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Grants

Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT


Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH


Funding Acknowledgements

BD, SH and ES declare no conflict of interest. PJC receives or has received research support in the past 3 years from NINDS, Bristol Myers-Squibb, Johnson and Johnson, AstraZeneca, Michael J Fox Foundation, Thome Foundation, and the Dystonia Foundation. PJC is an inventor on patents that protect different classes of M1 PAMs. He has consulted over the past 3 years for Pfizer and received compensation. Over the past 3 years, he has served on the Scientific Advisory Boards of Seaside Therapeutics, Michael J Fox Foundation, Stanley Center for Psychiatric Research Broad Institute (MIT/Harvard), Karuna Pharmaceuticals, Lieber Institute for Brain Development Johns Hopkins University, Clinical Mechanism (POCM) and Proof of Concept (POC) Consortium, Brain and Behavior Research Foundation, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder.