The muscarinic M4 acetylcholine receptor exacerbates symptoms of movement disorders

Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the matching efficacy of anticholinergic treatment in movement disorders seem to support this hypothesis. However, evidence from translational and clinical studies in movement disorders indicates that many features of this simple balance are lost, broken, or absent from movement disorders models or in imaging studies of patients with these disorders. This review reappraises the dopamine-acetylcholine balance hypothesis in light of recent evidence and describes how the Gαi/o coupled muscarinic M4 receptor acts in opposition to dopamine signaling in the basal ganglia. We highlight how M4 signaling can ameliorate or exacerbate movement disorders symptoms and physiological correlates of these symptoms in specific disease states. Furthermore, we propose future directions for investigation of this mechanisms to fully understand the potential efficacy of M4 targeting therapeutics in movement disorders. Overall, initial evidence suggest that M4 is a promising pharmaceutical target to ameliorate motor symptoms of hypo- and hyper-dopaminergic disorders.