Historically, the treatment of schizophrenia has centered around manipulation of the dopamine D2 receptor. In fact, all currently approved treatments for schizophrenia bind to dopamine D2 receptors to some degree. Unfortunately, while these dopaminergic agents effectively reduce psychosis by reducing dopamine in areas associated with psychosis, they are also associated with increased risk of motor symptoms due to dopamine reduction in motor regions of the brain. There is little evidence that these dopaminergic agents have much effect on the other domains of schizophrenia -the negative and cognitive symptoms. There is therefore growing interest in development of novel antipsychotic agents that do not directly affect dopamine D2 receptors. One such area of study includes muscarinic receptors, especially the M1 and M4 receptors. By selectively targeting these receptors, there is upstream regulation of dopaminergic signaling specifically in the nucleus accumbens (Figure). Preclinical and clinical data suggest that that these selective muscarinic ligands or positive allosteric modulators (PAMs) have benefits in reducing all 3 domains of schizophrenia -positive, negative, and cognitive- without increasing risk for movement disorders. There are currently 2 such muscarinic agents in advanced development: KarXT (an M1/M4 agonist) and emraclidine (an M4 PAM). As we move beyond the dopamine D2 focus of treating schizophrenia, there is great hope for these novel agents

Stimulation of the postsynaptic M1 receptor located on GABAergic neurons in the cortex causes inhibition of glutamatergic pyramidal cells. Glutamate release and subsequent stimulation of dopaminergic cells in the ventral tegmental area (VTA) is thereby reduced, leading to less dopamine release in the nucleus accumbens. Activation of dopaminergic neurons in the VTA is also inhibited when presynaptic M4 receptors are stimulated. Activation of the M4 receptor induces reduced release of acetylcholine (ACh); with less ACh to bind M5 receptors located on dopaminergic neurons, the dopaminergic neurons are not as active and less dopamine is released in the nucleus accumbens. Additionally, binding of an agonist or positive allosteric modulator (PAM) to presynaptic M4 receptors located on cholinergic neurons in the nucleus accumbens inhibits release of ACh. With less ACh to act on presynaptic nicotinic acetylcholine receptors (nACh) located on dopaminergic neurons, there is also reduction of dopamine release.

Reference:

Yohn SE et al. Trends Pharmacologic Sci 2022;43(12):1098-112. Abstract.