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Novel Antischizophrenia Treatments pp 233–265Cite as

Muscarinic Mechanisms in Psychotic Disorders

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 213))

Abstract

Schizophrenia is a devastating disease with several broad symptom clusters and the current monoamine-based treatments do not adequately treat the disease, especially negative and cognitive symptoms. A proposed alternative approach for treating schizophrenia is through the use of compounds that activate certain muscarinic receptor subtypes, the so-called muscarinic cholinergic hypothesis theory. This theory has been revitalized with a number of recent and provocative findings including postmortem reports in schizophrenia patients showing decreased numbers of muscarinic M1 and M4 receptors in brain regions associated with schizophrenia as well as decreased muscarinic receptors in an in vivo imaging study. Studies with M4 knockout mice have shown that there is a reciprocal relationship between M4 and dopamine receptor function, and a number of muscarinic agonists have shown antidopaminergic activity in a variety of preclinical assays predictive of antipsychotic efficacy in the clinic. Furthermore, the M1/M4 preferring partial agonist xanomeline has been shown to have antipsychotic-like and pro-cognitive activity in preclinical models and in clinical trials to decrease psychotic-like behaviors in Alzheimer’s patients and positive, negative, and cognitive symptoms in patients with schizophrenia. Therefore, we propose that an agonist with M1 and M4 interactions would effectively treat core symptom clusters associated with schizophrenia. Currently, research is focused on developing subtype-selective muscarinic agonists and positive allosteric modulators that have reduced propensity for parasympathetic side-effects, but retain the therapeutic benefit observed with their less selective predecessors.

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  1. Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN, 46285, USA

    David L. McKinzie

  2. Euthymics Bioscience Inc., 43 Thorndike Street Suite S1-3, Cambridge, MA, 02141, USA

    Frank P. Bymaster

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  1. Dept. Psychiatry, University of California San Diego, Gilman Drive 9500, La Jolla, 92093-0804, California, USA

    Mark A. Geyer

  2. Institut für Pharmakologie, Universität, Neuroscience Research, Abbott GmbH & Co. KG, Knollstraße, Ludwigshafen, 67061, Germany

    Gerhard Gross

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McKinzie, D.L., Bymaster, F.P. (2012). Muscarinic Mechanisms in Psychotic Disorders. In: Geyer, M., Gross, G. (eds) Novel Antischizophrenia Treatments. Handbook of Experimental Pharmacology, vol 213. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25758-2_9

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