Understanding Why Muscarinic Receptor Agonists Have Antipsychotic Properties

Abstract

Background

All current antipsychotics have direct dopamine (DA) D₂ receptor activity, which is associated with problems such as dysphoria, EPS, or prolactin elevation. Muscarinic receptor agonists have shown antipsychotic-like activity across preclinical models and clinical trials. This poster reviews preclinical evidence as to how muscarinic receptor agonists, such as the M₁/M₄ preferring agonist xanomeline, might have clinically relevant antipsychotic effects.

Objectives

Highlight the novel mechanisms through which muscarinic receptor agonists are associated with antipsychotic effects without having any direct dopaminergic D₂ receptor activity.

Key Points

The muscarinic receptor family is composed of 5 G protein-coupled receptors (GPCRs). One of the leading hypotheses explaining the antipsychotic activity of muscarinic receptor agonists is preclinical studies of muscarinic receptor modulation of those DA circuits associated with psychosis. Both M₁ and M₄ receptors are expressed in DA neural circuits implicated in psychosis, and provide unique regulation of these circuits. Xanomeline has both functional M₁ and M₄ receptor agonist activity, and shows robust antipsychotic-like effects in several animal models that require the presence of functional M₁ and M₄ receptors. M₄ receptors are autoreceptors on cholinergic neurons that regulate DA circuits in two locations: ventral tegmental area (VTA) and nucleus accumbens (NAc). Cholinergic-rich neurons from the hindbrain at the VTA, where they release acetylcholine (ACh) into DA-rich synaptic spaces. M₄ autoreceptors are present on these neurons, and their activation reduces ACh release and lowers ambient synaptic ACh concentrations, leading to reduced DA cell firing. Cholinergic interneurons residing in the NAc also express M₄ autoreceptors. These ACh interneurons regulate ACh release with M₄ activation also turning off ACh release. Therefore, M₄ receptors serve as DA regulators at VTA and NAc, both key sites for dopamine’s role in psychotic processes. M₁ receptors regulate DA circuits in a different, “top down” manner. M₁ receptors are found on cortical inhibitory interneurons. When activated, inhibitory drive onto excitatory output neurons is enhanced, which leads to reduced excitatory tone to VTA DA neurons.

Summary

Over the last 25 years, a growing body of evidence has shown potential for muscarinic receptor agonists to become a new class of medicines with potent antipsychotic activity. Preclinical data at micro-and macro-circuit levels suggest that the M₁ and M₄ receptor subtypes are most relevant in the regulation of DA circuits. The antipsychotic effects of muscarinic agonists effects may arise from influencing these key muscarinic receptor subtypes that are integral to the regulation of DA neural circuits. In summary, there has been great progress in understanding the potential for muscarinic receptor agonists for the treatment of psychosis.

Funding

Karuna Therapeutics