Pharmacology And Physiology Of The Substantia Nigra And

多巴胺系统对基底神经节中适当的信息处理至关重要。这种神经元系统的功能障碍与许多神经系统疾病的病因学有关，包括帕金森病、迟发性运动障碍、亨廷顿舞蹈病和注意力缺陷多动障碍。在2002财政年度，对多巴胺在基底神经节功能中的作用的研究集中在多巴胺在调节完整大鼠和帕金森病啮齿动物模型中不同基底神经节核的放电率和放电模式中的作用。目前感兴趣的是这样一种假设，即多巴胺受体刺激的改变通过调节基底神经节内以及基底神经节与其他核团之间在各种时间尺度上的活动同步的机制来调节运动（以及潜在的其他多巴胺调节的功能，如注意力和可塑性）。生理神经药理学部分的先前研究集中于调查固定清醒大鼠整个基底神经节的张力活性神经元活动中的新型超低振荡。这些研究以前已经证明：1）全身给予增加多巴胺受体刺激的药物，如阿扑吗啡，安非他明，可卡因和选择性多巴胺摄取阻滞剂，增加了这些振荡的频率，2）全身麻醉剂几乎消除了它们，3）多巴胺激动剂刺激后，基底神经节神经元对表现出更多的相关多秒振荡活动。此外，海马体中的θ节律（4-7 Hz）活动和运动皮层中的δ活动的爆发与基底神经节中的这些多秒放电率振荡相关。在2002财年，配对记录的单个神经元结合局部场电位的同时记录表明，增加多巴胺受体刺激也显着影响这些超低频振荡的相位关系，基底神经节内，基底神经节之间在不同的半球和皮质，基底神经节和海马之间。当苍白球被用作参考时，与大多数其他大脑区域的相位关系随着多巴胺受体刺激的增加而变得强烈同步。然而，丘脑底核表现出不同的反应，保持与苍白球的混合相/反相的关系后，增加和减少多巴胺受体刺激。这一观察结果支持了丘脑底核作为基底神经节输入的独立来源的新兴作用，而不是简单地作为一个“通过”核传递信息从苍白球到输出核，因为已经假设在流行的基底神经节模型。这一观点得到了以下观察结果的支持：丘脑底核的损伤破坏了苍白球和黑质网状部之间的相位关系。多巴胺在超慢时间尺度上改变各种中枢神经系统结构活性的作用部位已被研究，并显示为那些多巴胺受体，主要在纹状体中，其因多巴胺细胞损伤而失去神经支配。 超低频振荡在这些大脑区域内和之间组织更快频率的振荡活动中的作用是目前的焦点。今年开始的工作是研究多巴胺受体刺激的改变对与运动和震颤相关的频率活动的同步性和连贯性的影响。多巴胺受体刺激对基底神经节内和基底神经节与清醒行为啮齿动物制剂中的其他区域之间的活动同步的影响正在研究中使用光谱和小波分析技术的两个制剂。长期植入的电极被用来检查清醒行为大鼠的基底神经节中的神经元活动，并与影响多巴胺受体功能的药物治疗相结合。单个单位和局部场电位活动也被记录从大鼠训练挂在吊索，以确定在基底神经节和其他系统的神经元活动的同步多巴胺受体模拟的变化的影响。这种准备允许使用更高电阻的电极，其位置可以在记录期间进行调整。迄今为止的记录显示，这些动物也表现出可变的变化，在超低的时间尺度与基底神经节和海马活动之间的相关性多巴胺受体操纵的情况下，放电率。运动之间的关系，和活动的同步增加的时期，如局部场电位的幅度增加所示，正在研究中。此外，正在研究一系列麻醉剂对缓慢振荡（δ范围，0.3 - 4.0 Hz）变化的影响，以确定多巴胺影响麻醉制剂中这些参数的潜力。在这个时间尺度上的活动已经在麻醉动物的丘脑皮层回路中进行了广泛的研究，但在基底神经节中没有。这些研究应给予洞察基底神经节丘脑皮质的关系。已经观察到麻醉剂之间的显著差异，氨基甲酸乙酯是最适合研究药物对这些参数影响的药物。未来的研究将检查黑质纹状体病变，帕金森氏症的啮齿动物模型，对这些参数的影响，并进一步调查的潜在重要性，在运动障碍的放电模式的变化，而不是率本身。

The dopamine system is critical to appropriate information processing in the basal ganglia. Dysfunction of this neuronal system has been implicated in the etiology of many neurological diseases, including Parkinson's disease, tardive dyskinesia, Huntington's chorea and attention deficit hyperactivity disorder. Investigations into the role of dopamine in basal ganglia function in FY2002 have focused on the role of dopamine in regulating firing rate and firing patterns in different basal ganglia nuclei in intact rats and in a rodent model of Parkinson's disease. Currently of interest is the hypothesis that alterations in dopamine receptor stimulation regulate movement (and potentially other dopamine-modulated functions, such as attention and plasticity) through mechanisms regulating synchronization of activity within the basal ganglia, and between basal ganglia and other nuclei, on a variety of time scales. Previous studies in the Physiological Neuorpharmacology Section have focused on investigation of a novel ultraslow oscillation in the activity of tonically-active neurons throughout the basal ganglia of immobilized, awake rats. These studies have previously demonstrated that: 1) systemic administration of drugs that increase dopamine receptor stimulation such as apomorphine, amphetamine, cocaine and selective dopamine uptake blockers increase the frequency of these oscillations, 2) general anesthetics virtually eliminate them, and 3) pairs of basal ganglia neurons demonstrate a greater number of correlated multisecond oscillatory activity after dopamine agonist stimulation. In addition, bursts of theta rhythm (4-7 Hz) activity in the hippocampus and delta activity in the motor cortex correlate with these multisecond firing rate oscillations in the basal ganglia. In Fiscal Yeal 2002, paired recordings of single neurons combined with simultaneous recordings of local field potential have shown that increased dopamine receptor stimulation also dramatically affects the phase relationship of these ultraslow oscillations within basal ganglia, between basal ganglia in different hemispheres and between cortex, basal ganglia and hippocampus. When the globus pallidus is used as the reference, phase relationships with most other brain regions became strongly synchronized with increased dopamine receptor stimulation. However, the subthalamic nucleus shows a different response, maintaining a mixed phase/antiphase relationship with the globus pallidus after both increases and decreases in dopamine receptor stimulation. This observation supports the emerging role of the subthalamic nucleus as an independent source of input to the basal ganglia, as opposed to being simply a "pass-through" nucleus conveying information from globus pallidus to output nuclei, as has been postulated in popular basal ganglia models. This view was supported by observation that phase relationships between the globus pallidus and substantia nigra pars reticulata were disrupted by lesion of the subthalamic nucleus. The site of action of dopamine in altering activity in various central nervous system structures on a ultraslow time scale has been investigated and shown to be those dopamine receptors, predominately in the striatum, which are denervated with dopamine cell lesion. The role of the ultraslow oscillations in organized faster frequencies of oscillatory activity within and between these brain regions is a current focus. Work was initiated this year on studies of effects of alterations in dopamine receptor stimulation on synchronization and coherence of activity in frequencies shown to be relevant to movement and tremor. Effects of dopamine receptor stimulation on synchronization of activity within the basal ganglia and between basal ganglia and other regions in awake behaving rodent preparations is being investigated in two preparations using spectral and wavelet analyses techniques. Chronically implanted electrodes are being used to examine neuronal activity in the basal ganglia of awake behaving rats in conjunction with drug treatments to affect dopamine receptor function. Single unit and local field potential activity is also being recorded from rats trained to hang in slings to determine effects of alterations in dopamine receptor simulation on synchronization of neuronal activity in basal ganglia and other systems. This preparation allows the use of higher resistance electrodes whose location can be adjusted during the recordings. Recordings to date show these animals also demonstrate variable changes in firing rate on ultraslow time scales with correlations between basal ganglia and hippocampal activity in the absence of dopamine receptor manipulation. Relationships between movement, and periods of increased synchronization of activity, as indicated by increased amplitude in local field potential, are being examined. In addition effects of a series of anesthetics on alterations in slow oscillations (delta range, 0.3 - 4.0 Hz) are being studied to determine the potential for dopamine to affect these parameters in anesthetized preparations. Activity in this time scale has been studied extensively in anesthetized animals in thalamocortical circuits, but not in the basal ganglia. These studies should give insight into basal ganglia-thalamocortical relationships. Marked differences between anesthetics have been observed, with urethane being the agent most amenable to study of drug effects on these parameters. Future studies will examine the effects of nigrostriatal-lesion, a rodent model of parkinsonism, on these parameters and further investigate the potential importance of changes in firing pattern, as opposed to rate per se, in movement disorders.