Exploring the Emerging Role of M4 Muscarinic Acetylcholine Receptors in Understanding and Treating Schizophrenia

Positive symptoms of schizophrenia (ie, psychosis) are driven by dopaminergic hyperactivity. Currently approved antipsychotics block postsynaptic D2 dopamine receptors but do not target the underlying pathophysiology of elevated presynaptic dopamine release (eg, in the associative striatum), which is associated with psychosis. Global D2 dopamine receptor blockade can result in adverse effects that are associated with increased comorbidities and decreased treatment adherence. The M4 muscarinic acetylcholine receptor (mAChR), a subtype of the G-protein–coupled acetylcholine muscarinic receptor family, is thought to play a role in regulating dopamine release. A literature review was performed to understand the potential role of M4 mAChR activation in reducing presynaptic dopamine release and the potential therapeutic applications for psychosis in schizophrenia. M4 receptors are highly expressed in the central nervous system, including in key striatal networks thought to drive psychosis. M4 activation may regulate striatal dopamine release through two presynaptic mechanisms: cholinergic brainstem projections to midbrain dopamine neurons that project to the associative striatum, and by cholinergic interneurons in the striatum. Historically, selective M4 activation has been difficult to achieve with muscarinic agonists as the binding site is conserved across mAChR subtypes. Since the allosteric binding site differs between mAChR subtypes, positive allosteric modulators may be a promising approach to selectively activating M4 receptors while avoiding broader mAChR activation and associated side effects. This research highlights the potential role of selective M4 mAChR activation in presynaptic regulation of excessive dopamine release in psychosis associated with schizophrenia, which may extend treatment options as M4-selective therapies become available.