Department of Psychology, University of Michigan, 530 Church Street, Ann Arbor, MI, 48103, USA.
Psychopharmacology (Berl). 2021 Jul;238(7):1953-1964. doi: 10.1007/s00213-021-05822-x. Epub 2021 Mar 18.
In addition to the disease-defining motor symptoms, patients with Parkinson's disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine (DA) loss, to the resulting disruption of the attentional control of balance and complex movements. Rats with dual cholinergic-DA losses ("DL rats") were previously demonstrated to model PD falls and associated impairments of gait and balance.
We previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats.
Prior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. As before, DL rats fell more frequently than sham-operated control rats. Treatment of DL rats with TAK-071 reduced falls from the rotating rod and the rotating zigzag rod, specifically when the angled part of the zigzag segment, upon entering, was at a steep, near vertical angle.
TAK-071 may benefit complex movement control, specifically in situations which disrupt the patterning of forward movement and require the interplay between cognitive and motor functions to modify movement based on information about the state of dynamic surfaces, balance, and gait.
除了疾病定义的运动症状外，帕金森病（PD）患者还表现出行走功能障碍、姿势不稳和易跌倒。这些多巴胺（DA）替代疗法抵抗的症状部分归因于基底前脑（BF）胆碱能神经元的丧失，并且与纹状体 DA 丧失相互作用，导致平衡和复杂运动的注意力控制中断。先前已经证明双重胆碱能-DA 丧失的大鼠（“DL 大鼠”）可以模拟 PD 跌倒以及相关的步态和平衡障碍。
我们之前发现，毒蕈碱 M1 阳性变构调节剂（PAM）TAK-071 改善了 BF 胆碱能丧失大鼠的注意力表现。在这里，我们测试了 TAK-071 降低 DL 大鼠跌倒率的假设。
在 DL 手术之前，雌性大鼠接受了穿越旋转直杆和带有两个之字形段的杆的训练。DL 大鼠在手术后重新熟悉此类穿越，并在越来越苛刻的测试条件下进行了 7 天的测试。TAK-071（0.1、0.3mg/kg，po）在 7 天的测试期间每天测试前给药。与以前一样，DL 大鼠跌倒的频率高于假手术对照大鼠。用 TAK-071 治疗 DL 大鼠可减少从旋转杆和旋转之字形杆上跌倒，特别是当之字形段的倾斜部分进入时，处于陡峭、近乎垂直的角度。
TAK-071 可能有益于复杂运动控制，特别是在破坏前进运动模式并需要认知和运动功能相互作用的情况下，根据有关动态表面、平衡和步态的状态信息来修改运动。
