Muscarinic mechanisms in psychotic disorders

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 M 1 and M 4 receptors in brain regions associated with schizophrenia as well as decreased muscarinic receptors in an in vivo imaging study. Studies with M 4 knockout mice have shown that there is a reciprocal relationship between M 4 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 M 1/M 4 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 M 1 and M 4 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. © 2012 Springer-Verlag Berlin Heidelberg.