Activation of M4 muscarinic receptors in the striatum reduces tic‐like behaviours in two distinct murine models of Tourette syndrome

Background and Purpose Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M 1 and/or M 4 receptors—the two most abundant muscarinic receptors in the striatum—reduced tic‐related behaviours in mouse models of TS. Experimental Approach Studies were conducted using CIN‐d and D1CT‐7 mice, two TS models characterized by early‐life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M 1 /M 4 receptor agonist, on tic‐like and other TS‐related responses. Then, we examined whether xanomeline effects were reduced by either M 1 or M 4 antagonists or mimicked by the M 1 /M 3 agonist cevimeline or the M 4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M 1 and M 4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c‐Fos. Key Results Systemic and intrastriatal xanomeline reduced TS‐related behaviours in CIN‐d and D1CT‐7 mice. Most effects were blocked by M 4 , but not M 1 , receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline‐like ameliorative effects in both models. M 4 , but not M 1 , receptors were down‐regulated in the striatum of CIN‐d mice. Additionally, VU0467154 reduced striatal c‐Fos levels in these animals. Conclusion and Implications Activation of striatal M 4 , but not M 1 , receptors reduced tic‐like manifestations in mouse models, pointing to xanomeline and M 4 PAMs as novel putative therapeutic strategies for TS.