Sub-type selective muscarinic acetylcholine receptor modulation for the treatment of parkinsonian tremor

Abstract

Parkinsons Disease is characterized by hallmark motor symptoms including resting tremor, akinesia, rigidity, and postural instability. In patient surveys of Parkinsons Disease symptoms and quality of life, tremor consistently ranks among the top concerns of patients with disease. However, the gold standard of treatment, levodopa, has inconsistent or incomplete anti-tremor effects in patients, necessitating new therapeutic strategies to help relieve this burden. Non-selective anti-muscarinic acetylcholine receptor therapeutic agents which target each of the 5 muscarinic receptor subtypes have been used as an adjunct therapy in this disease, as well as other movement disorders, and have been shown to have anti-tremor efficacy. Despite this, anti-muscarinic therapy is poorly tolerated due to adverse effects. Recent pharmacological advances have led to the discovery of muscarinic subtype selective antagonists that may keep the anti-tremor efficacy of non-selective compounds, while reducing or eliminating adverse effects. Here, we directly test this hypothesis using pharmacological models of parkinsonian tremor combined with recently discovered selective positive allosteric modulators and antagonists of the predominant brain expressed muscarinic receptors M1, M4, and M5. Surprisingly, we find that selective modulation of M1, M4, or M5 does not reduce tremor in these pre-clinical models, suggesting that central or peripheral M2 or M3 receptors may be responsible for the anti-tremor efficacy of non-selective anti-muscarinic therapies currently used in the clinic.