Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency.
Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency.
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DOI：
10.1007/s12035-018-1256-9
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发表时间：
2019-04
影响因子：
5.1
通讯作者：
Pruett BS
中科院分区：
文献类型：
--
作者：
Salvatore MF;McInnis TR;Cantu MA;Apple DM;Pruett BS
运动频率或体力活动减少(运动迟缓)在老年人中发病率很高。然而，在老年人类、非人灵长类或啮齿动物中，纹状体酪氨酸羟化酶(TH)的丢失并没有达到帕金森病中与运动迟缓相关的~80%的丢失阈值。中度纹状体多巴胺(DA)的丢失，无论是在TH抑制或TH表达减少之后，可能不会影响运动频率。相反，在帕金森病中，黑质(SN)的中度DA或TH丢失与运动迟缓发作时黑质TH的丢失程度相似(~40%)。在老年大鼠中，黑质中TH和DA的单独表达增加增加了运动频率，这表明与衰老相关的黑质中TH和DA的丢失与衰老相关的运动迟缓或体力活动减少有关。为了验证这一假说，在受试者内部设计中，在幼年(6个月大)大鼠身上使用双侧导管靶向黑质，以评估抑制黑质TH对运动频率和速度的影响。TH抑制剂α-甲基-对酪氨酸(AMPT)在给药后45-150min使黑质DA减少~40%，但对纹状体、伏隔核或邻近腹侧被盖区的DA无影响。记录每个受试者在注射黑质生理盐水或安普特后3小时内的野外活动情况。在黑质特异性DA减少期间，运动频率显著降低，但运动速度无明显变化。这些结果表明，在增龄过程中观察到的黑质中DA或TH的丢失是运动频率降低的一种中心机制。
Reduced movement frequency or physical activity (bradykinesia) occurs with high prevalence in the elderly. However, loss of striatal tyrosine hydroxylase (TH) in aging humans, non-human primates, or rodents does not reach the ~80% loss threshold associated with bradykinesia onset in Parkinson’s disease. Moderate striatal dopamine (DA) loss, either following TH inhibition or decreased TH expression, may not affect movement frequency. In contrast, moderate DA or TH loss in the substantia nigra (SN), as occurs in aging, is of similar magnitude (~40%) to nigral TH loss at bradykinesia onset in Parkinson’s disease. In aged rats, increased TH expression and DA in SN alone increases movement frequency, suggesting aging- related TH and DA loss in the SN contributes to aging-related bradykinesia or decreased physical activity. To test this hypothesis, the SN was targeted with bilateral guide cannula in young (6 months old) rats, in a within-subjects design, to evaluate the impact of nigral TH inhibition on movement frequency and speed. The TH inhibitor, α-methyl-p-tyrosine (AMPT) reduced nigral DA (~40%) 45–150 min following infusion, without affecting DA in striatum, nucleus accumbens, or adjacent ventral tegmental area. Locomotor activity in the open-field was recorded up to 3 hours following nigral saline or AMPT infusion in each test subject. During the period of nigra-specific DA reduction, movement frequency, but not movement speed, was significantly decreased. These results indicate that DA or TH loss in the SN, as observed in aging, contributes as a central mechanism of reduced movement frequency.
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影响因子：
5
作者：
Arnold JC;Salvatore MF
通讯作者：
Salvatore MF
影响因子：
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作者：
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