PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

晚期高血压患者左旋多巴运动反应改变的研究 帕金森病患者发现潜伏期至峰值运动反应 与症状持续时间和严重程度密切相关。结果是 提示代偿性突触前机制，尤其是加速的 多巴胺的代谢和释放，导致帕金森氏症的缺失 症状，直到大多数黑质纹状体多巴胺能神经元已经退化。 在一项相关的实验室研究中，左旋多巴治疗帕金森病 稳定破坏其95%以上多巴胺能的大鼠 神经元导致左旋多巴持续时间的进行性缩短 运动特效。这种反应的变化，就像是疲劳 在帕金森氏症患者中发生的现象并不少见 严重损毁大鼠，表明突触后改变丢失 多巴胺神经元必须超过相对较高的阈值才能使用左旋多巴 治疗产生的变化，显然是在突触后水平， 有利于快速出现疲软波动。后续的 临床研究证实，与人们长期以来的看法相反， 节后改变，可能涉及相对可塑性的改变 纹状体的多巴胺感受器系统也是缩短的主要原因 在导致磨损波动的左旋多巴作用持续时间内 在帕金森病患者身上。该科以前的研究表明 谷氨酸系统改变运动反应的能力 多巴胺能刺激。此外，我们发现反复使用左旋多巴 给药下调D1多巴胺受体介导的反应， 上调由D2受体介导的受体，并逐渐减少 左旋多巴的运动反应持续时间。急性联合治疗与 非竞争性NMDA拮抗剂MK-801完全逆转了这一切 变化，这表明NMDA受体介导的机制有助于 与慢性左旋多巴治疗相关的反应变化 NMDA拮抗剂可逆转运动反应并发症 接受长期的左旋多巴治疗。自皮质退行性变以来 在阿尔茨海默病中，谷氨酸能投射是一个一致的发现， 我们评估了谷氨酸系统刺激的可能性 给予有症状的好处。环丝氨酸，一种间接的激动剂 (NMDA)谷氨酸受体对心肌细胞的作用不一致 神经心理结果指标，表明短期内 NMDA介导的谷氨酸能传递的增强可能不能证明 对这种疾病的对症治疗很有用。

Studies of the altered motor responses to levodopa occurring in advanced Parkinsonian patients revealed that the latency-to-peak motor response correlated closely with symptom duration and severity. The results suggest that compensatory presynaptic mechanisms, especially accelerated dopamine turnover and release, contribute to the absence of Parkinsonian symptoms until most nigrostriatal dopaminergic neurons have degenerated. In a related laboratory investigation, levodopa treatment of Parkinsonian rats with stable destruction of more than 95% of their dopaminergic neurons leads to a progressive shortening in the duration of levodopa's motor effects. This response alteration, resembling the wearing-off phenomena that develop in Parkinsonian patients, did not occur in less severely lesioned rats, suggesting that postsynaptic changes loss of dopamine neurons must exceed a relatively high threshold before levodopa treatment produces changes, evidently at the postsynaptic level, that favor the rapid appearance of wearing-off fluctuations. A subsequent clinical study confirmed that, contrary to long-held beliefs, postjunctional alterations, possibly involving relatively plastic striatal dopaminoceptive systems, also account for most of the shortening in the duration of levodopa action that underlie wearing-off fluctuations in parkinsonian patients. Previous studies by the Section demonstrated the ability of the glutamate system to alter motor responses to dopaminergic stimulation. In addition, we found that repeated levodopa administration down-regulated D1 dopamine receptor mediated responses, up~regulated those mediated by D2 receptors, and progressively reduced the duration of the motor response to levodopa. Acute co-treatment with the noncompetitive NMDA antagonist MK-801 completely reversed all these changes, suggesting that NMDA receptor-mediated mechanisms contribute to the response changes associated with chronic levodopa treatment and that NMDA antagonists act to reverse the motor response complications attending long-term levodopa therapy. Since degeneration of cortical glutamatergic projections is a consistent finding in Alzheimer's disease, we evaluated the possibility that glutamate system stimulation might confer symptomatic benefit. Cycloserine, an indirect agonist at certain (NMDA) glutamate receptors, had no consistent effect on neuropsychological outcome measures, suggesting that short-term potentiation of NMDA-mediated glutamatergic transmission may not prove useful in the symptomatic treatment of this disorder.