PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

(1)磨损现象，通常是最初的运动并发症， 左旋多巴治疗的帕金森病患者，已完全归因于 多巴胺（DA）储存能力的丧失， 多巴胺能神经元变性然而，最近的临床前研究表明， 怀疑这一观点，因为持续时间的运动效果的一个单一的 在通过固定DA系统损伤而导致帕金森病的大鼠中的左旋多巴剂量 在每日左旋多巴治疗过程中减少。初步 在用直接DA激动剂治疗的帕金森病患者中的观察， 阿扑吗啡，进一步支持了连接后改变的观点， 由于间歇性左旋多巴治疗， 磨损波动的发病机制。这些改变似乎 相对塑性，因为连续输注左旋多巴10天 将左旋多巴的作用持续时间缩短30%， 麦角乙脲是一种多巴胺激动剂，其作用超过90%。 (2)支持突触前机制起补偿作用的证据 帕金森病患者DA神经元丢失的原因来自临床 研究表明，注射左旋多巴和 峰值抗帕金森反应随着疾病严重程度的进展而下降。没有 阿扑吗啡直接作用于 刺激突触后受体初步观察显示 COMT抑制剂可以显著延长抗帕金森病的时间， 左旋多巴的作用，而不增加与 高多巴胺能刺激 (3)锥体外系运动功能似乎受到 神经系统。左旋多巴间歇给药 帕金森病大鼠，上调D2 DA受体介导的功能， 下调由D1受体介导的那些。合成函数 通过D2通路的纹状体输出可能有助于 运动并发症的发病机制。 急性给予MK~801，a 选择性NMDA拮抗剂，正常化的功能变化， D1和D2系统;阻断AMPA谷氨酸受体的药物没有 这种效果。事实上，AMPA和NMDA拮抗剂对人的神经细胞产生相反的作用。 由多巴胺能拮抗剂诱导的僵住症。 (4)假设谷氨酸替代可能导致症状性 有益于阿尔茨海默病患者， 预测已经退化，由行政部门评估， 环丝氨酸这种部分间接的NMDA激动剂没有一致的作用 对认知功能的影响

(1) Wearing-off phenomena, generally the initial motor complication in levodopa-treated Parkinsonian patients, have been attributed solely to the loss of dopamine (DA) storage capacity as a consequence of dopaminergic neuron degeneration. However, recent preclinical studies cast doubt on this view, since the duration of the motor effects of a single levodopa dose in rats rendered Parkinsonian by a fixed DA system lesion decrease during the course of daily levodopa therapy. Preliminary observations in Parkinsonian patients treated with the direct DA agonist, apomorphine, further support the view that post-junctional alterations resulting from intermittent levodopa treatment contribute substantially to the pathogenesis of wearing-off fluctuations. These changes appear relatively plastic, since a continuous infusion of levodopa for 10 days prolongs levodopa's duration of action by 30% and a 3~month infusion of lisuride, a DA agonist, does so by over 90%. (2) Evidence in support of presynaptic mechanisms operating to compensate for the loss of DA neurons in Parkinsonian patients derives from clinical studies showing the interval between the injection of levodopa and its peak antiparkinsonian response declines as disease severity advances. No change in this interval occurs with apomorphine which acts by directly stimulating postsynaptic receptors. Preliminary observations now suggest that a COMT inhibitor may substantially prolong the antiparkinsonian action of levodopa without increasing adverse effects associated with hyperdopaminergic stimulation. (3) Extrapyramidal motor function appears potently regulated by glutamatergic mechanisms. Intermittent levodopa administration to Parkinsonian rats, upregulates D2 DA receptor-mediated functions and down-regulates those mediated by D1 receptors. Resultant funneling of striatal output through the D2 pathway could contribute to the pathogenesis of motor complications. Acutely administered MK~801, a selective NMDA antagonist, normalizes the functional changes in both the D1 and D2 systems; drugs that block AMPA glutamate receptors do not have this effect. Indeed, AMPA and NMDA antagonists exert opposite effects on catalepsy induced by dopaminergic antagonists. (4) The hypothesis that glutamate replacement might confer symptomatic benefit to Alzheimer's disease patients whose cortical glutamatergic projections have degenerated, was evaluated by administration of cycloserine. This partial indirect NMDA agonist had no consistent effect on cognitive function.