Abstract：
OBJECTIVE: 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 M1 and/or M4 receptors-the two most abundant muscarinic receptors in the striatum-reduced tic-related behaviours in mouse models of TS.
METHODS: 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 M1/M4 receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos.
RESULTS: Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models. M4, but not M1, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals.
CONCLUSIONS: Activation of striatal M4, but not M1, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.
METHODS: 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 M1/M4 receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos.
RESULTS: Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models. M4, but not M1, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals.
CONCLUSIONS: Activation of striatal M4, but not M1, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.
摘要：
目的：目前治疗抽动症（TS）的药物治疗通常不令人满意且耐受性差，强调需要新的治疗方法。已表明纹状体乙酰胆碱不足会导致个体发育。因此，我们测试了在TS小鼠模型中是否激活M1和/或M4受体-纹状体减少的tic相关行为中最丰富的两种毒蕈碱受体。
方法：使用CIN-d和D1CT-7小鼠进行研究，两种TS模型的特征是纹状体胆碱能中间神经元的早期生命消耗和皮质神经增强，分别。首先,我们测试了全身和纹状体内黄线的效果，一种选择性M1/M4受体激动剂，关于tic-like和其他与TS相关的响应。然后，我们检查了M1或M4拮抗剂是否降低了xanomeline效应,或M1/M3激动剂cevimeline或M4阳性变构调节剂(PAM)VU0467154是否模仿了xanomeline效应.最后,我们测量了M1和M4受体的纹状体水平，并评估了VU0461754对神经标志物活性c-Fos纹状体表达的影响。
结果：在CIN-d和D1CT-7小鼠中，系统和纹状体内黄线降低了TS相关行为。大多数作用被M4阻断，而不是M1受体拮抗剂阻断。VU0467154，但不是cevimeline，在这两个模型中都引起了黄线样的改善作用。在CIN-d小鼠的纹状体中，M4而不是M1受体被下调。此外,VU0467154降低了这些动物的纹状体c-Fos水平。
结论：在小鼠模型中，纹状体M4而不是M1受体的激活减少了tic样表现，指出xanomeline和M4PAMs是TS的新的推定治疗策略。
方法：使用CIN-d和D1CT-7小鼠进行研究，两种TS模型的特征是纹状体胆碱能中间神经元的早期生命消耗和皮质神经增强，分别。首先,我们测试了全身和纹状体内黄线的效果，一种选择性M1/M4受体激动剂，关于tic-like和其他与TS相关的响应。然后，我们检查了M1或M4拮抗剂是否降低了xanomeline效应,或M1/M3激动剂cevimeline或M4阳性变构调节剂(PAM)VU0467154是否模仿了xanomeline效应.最后,我们测量了M1和M4受体的纹状体水平，并评估了VU0461754对神经标志物活性c-Fos纹状体表达的影响。
结果：在CIN-d和D1CT-7小鼠中，系统和纹状体内黄线降低了TS相关行为。大多数作用被M4阻断，而不是M1受体拮抗剂阻断。VU0467154，但不是cevimeline，在这两个模型中都引起了黄线样的改善作用。在CIN-d小鼠的纹状体中，M4而不是M1受体被下调。此外,VU0467154降低了这些动物的纹状体c-Fos水平。
结论：在小鼠模型中，纹状体M4而不是M1受体的激活减少了tic样表现，指出xanomeline和M4PAMs是TS的新的推定治疗策略。
