PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

1.左旋多巴治疗帕金森病并发的运动反应改变 疾病最初是由于纹状体多巴胺的丢失而引起的， 储存由于多巴胺能终末变性，但后来继发 反映了连接后的改变。在帕金森病大鼠中，突触后 变化，导致D2多巴胺的反应性增加 受体介导的纹状体传出和D1反应性降低 介导的投射，以间歇性的，但不是连续的， 拟多巴胺给药。由于纹状体D2受体结合 基本保持不变，D1仅轻度上调 受体，多巴胺感受肽能和下游受体的改变 据推测，神经系统是罪魁祸首。封锁NMDA 谷氨酸受体亚型对多巴胺产生不同的影响 激动剂诱导的旋转行为取决于多巴胺 受体亚型被激活，并且先前暴露于多巴胺 激动剂因此，NMDA拮抗剂可能会影响 拟多巴胺反应的临床和对抗某些运动 与长期左旋多巴治疗相关的并发症。 2.早期的研究表明， 左旋多巴和多巴胺的半衰期将提供预防以及 对帕金森病患者的姑息治疗。现在我们发现 新的儿茶酚-O-甲基转移酶抑制剂的联合给药 基本上抑制了对L-多巴-卡比多巴的反应， 显著影响不良反应的类型或严重程度。的 在帕金森病患者的治疗方案中加入他卡朋 因此应该证明在控制磨损波动方面是有用的， 其他运动反应并发症。 3.甘氨酸前药米拉塞米，可积极调节NMDA 受体介导的突触能传递，一过性增加 帕金森病患者的总体症状严重程度，进一步 支持了我们的观点， 受体亚型可能有助于治疗这种疾病。的 选择性kappa受体激动剂，spiradoline，用于评估 强啡肽能传递增强护理的临床效果 慢性左旋多巴给药帕金森病大鼠，产生的剂量 限制妨碍达到剂量水平的不良反应 接近影响啮齿动物运动表现的那些。

1. Altered motor responses complicating L-Dopa therapy of Parkinson's disease initially arise as a consequence of the loss of striatal dopamine storage due to dopaminergic terminal degeneration, but later secondarily reflect postjunctional alterations. In Parkinsonian rats, postsynaptic changes, leading to increased responsivity of D2 dopamine receptor-mediated striatal efferents and diminished responsivity of D1 mediated projections, occur with intermittent, but not continuous, dopaminomimetic administration. Since striatal D2 receptor binding remains essentially unchanged and there is only mild up-regulation of D1 receptors, alterations in dopaminoceptive peptidergic and downstream glutamatergic systems are presumably responsible. Blockade of the NMDA subtype of glutamate receptors exerted differential effects on dopamine agonist-induced rotational behavior that depend on which dopamine receptor subtype is activated and the previous exposure to dopamine agonists. NMDA antagonists might thus be expected to influence dopaminomimetic responses clinically and counter certain of the motor complications associated with chronic L-Dopa treatment. 2. Earlier studies suggested that drugs acting to extend the biologic half-life of L-Dopa and dopamine will confer prophylactic as well as palliative benefit to Parkinsonian patients. Now we find that coadministration of a novel inhibitor of catechol-O-methyltransferase substantially prolongs the response to L-Dopa-carbidopa without significantly affecting the type or severity of adverse effects. The addition of talcapone to the therapeutic regimen of Parkinsonian patients should thus prove useful in controlling wearing-off fluctuations and other motor response complications. 3. The glycine prodrug, milacemide, which positively modulates NMDA receptor-mediated glutamatergic transmission, transiently increased overall symptom severity in Parkinsonian patients, lending further support to our view that pharmaceuticals that block certain glutamate receptor subtypes may assist in the treatment of this disease. The selective kappa receptor agonist, spiradoline, given to evaluate the clinical effects of the enhanced dynorphinergic transmission attending chronic levodopa administration to parkinsonian rats, produced dose limiting adverse effects that precluded attainment of dose levels approximating those affecting rodent motor performance.