PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

我们的目标是开发更好的中枢神经系统药物治疗 基于递质机制与临床之间关系的疾病 功能 研究继续关注帕金森病， 老年痴呆症 在帕金森病中，中枢药代动力学或 药效学因素似乎是导致 左旋多巴在患者中的有效半衰期， 那些有开关现象的人 左旋多巴循环的稳定性 水平，持续左旋多巴或左旋多巴甲酯输注，或 持续释放制剂，迅速消除磨损反应; 开-关现象减少得更慢且更不完全。 D-1和D-2 多巴胺受体机制，临床前评估与其 这些运动波动的发病机制的潜在贡献， 出现复杂的相互作用：D-1受体刺激可能提供一种滋补剂， 背景允许D-2刺激的相位分量变成 有效 然而，在帕金森病患者中， 选择性D-1激动剂对运动功能无影响。 在阿尔茨海默氏症中，识别发射系统的努力 可能为对症治疗提供依据的异常， 最近强调皮质肽能神经元，特别是 生长抑素系统 这种神经肽的脊髓液水平是 大大低于控制水平;这些减少的幅度 与痴呆的严重程度以及PET确定的 皮质葡萄糖利用率，特别是在后顶叶 区 尽管如此，用强效生长抑素耗竭剂治疗， 部分旨在阐明这种肽能系统在 痴呆，显著增加血浆生长激素水平，但没有 影响认知或运动功能。

Our goal is to develop improved pharmacotherapies for central nervous sytem disorders based on the relation between transmitter mechanisms and clinical function. Investigations continue to focus on Parkinson's disease and Alzheimer's disease. In Parkinson's disease, alterations in central pharmacokinetic or pharmacodynamic factors appear responsible for the marked reductions in efficacy half-life of levodopa in patients with wearing-off and especially those with on-off phenomena. The stabilization of circulating levodopa levels, with continuous levodopa or levodopa methylester infusions or sustained release formulations, rapidly eliminates wearing-off responses; on-off phenomenon diminish more slowly and less completely. D-1 and D-2 dopamine receptor mechanisms, evaluated preclinically in relation to their potential contribution to the pathogenesis of these motor fluctuation, appear complexly interactive: D-1 receptor stimulation may provide a tonic background allowing the phasic component of D-2 stimulation to become effective. In parkinsonian patients, however, administration of a selective D-1 agonist failed to influence motor function. In Alzheimer's disease, efforts to identify transmitter system abnormalities which might provide a basis for symptomatic therapies have recently emphasized cortical peptidergic neurons, especially the somatostatin system. Spinal fluid levels of this neuropeptide are substantially below control levels; the magnitude of these reductions correlate closely with dementia severity as well as with PET determined rates of cortical glucose utilization, especially in the posterior parietal area. Nevertheless, treatment with a potent somatostatin depleting agent, designed in part to elucidate the role of this peptidergic system in dementia, significantly increased plasma growth hormone levels but had no effect on cognitive or motor function.