PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

多巴胺系统是基底节适当信息处理的关键。这种神经系统的功能障碍与许多神经系统疾病的病因有关，包括帕金森氏病、迟发性运动障碍、亨廷顿舞蹈症和注意缺陷多动障碍。2000财年对多巴胺在基底节功能中的作用的研究主要集中在多巴胺对正常大鼠和帕金森病啮齿动物模型不同基底节核团的放电频率和放电模式的调节作用。人们对神经系统中振荡放电模式的重要性越来越感兴趣。然而，大多数研究只检查了频率大于1赫兹的振荡结构的棘波序列。在细胞外单单位记录研究中，生理神经药理学部分发现，在被束缚的清醒大鼠中，4个不同基底节核团中的许多强直活动神经元在基线放电率上有缓慢的、反复的多秒振荡。这些研究已经证明：1)全身应用阿朴吗啡、安非他明和可卡因等增加多巴胺受体刺激的药物会增加这些振荡的频率，2)全身麻醉剂几乎消除了这些振荡，3)在多巴胺激动剂刺激后，基底节神经元显示出更多相关的多秒振荡活动。在1999财年，我们发现选择性多巴胺摄取阻滞剂也显著减少了基底节放电频率的振荡周期，而去甲肾上腺素和5-羟色胺摄取阻滞剂则没有显著影响。目前的理论认为，低剂量的兴奋剂，如苯丙胺和哌醋甲酯(利他林)，通过作用于多巴胺自身受体来减少儿茶酚胺能传递，从而减轻注意缺陷多动障碍患者的症状，但这些药物对基底神经节神经元放电频率的影响的研究与此相矛盾。这些广泛使用的疗法能够显著改变基底节活动的多秒振荡周期，这支持了儿茶酚胺能兴奋剂可能通过调节中枢活动的时间模式而影响运动和注意力过程的观点。已经评估了这些多巴胺调节的基底节活动的多秒振荡与大脑皮层活动的关系，以及丘脑神经元也表达这些缓慢振荡的可能性。数据显示，基底节的多秒振荡和丘脑神经元的放电率与EEG theta功率的变化相关，EEG theta功率是与注意力或唤醒相关的皮质活动指数。此外，全身给药的多巴胺激动剂加强了这种相关性，在帕金森氏病动物模型中，多巴胺细胞损伤后激动剂的作用增强。这些研究还显示了啮齿类动物内侧丘脑核与其在灵长类动物中的同源物之间的新的相似之处，灵长类动物是苍白球的内节。帕金森氏病的啮齿动物和灵长类动物模型与帕金森氏病患者的神经生理学数据之间令人印象深刻的相关性支持了啮齿动物研究结果与人类和非人类灵长类动物基底节功能的相关性。

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 FY2000 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. There has been a growing interest in the importance of oscillatory firing patterns in the nervous system. However, most studies have only examined spike trains for oscillatory structure at frequencies greater than 1 Hz. In extracellular single unit recording studies, the Physiological Neuorpharmacology Section has found that many tonically-active neurons in 4 different basal ganglia nuclei have slow, recurrent multisecond oscillations in baseline firing rate in immobilized, awake rats. These studies have previously demonstrated that: 1) systemic administration of drugs that increase dopamine receptor stimulation such as apomorphine, amphetamine, and cocaine increases 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 FY 99, we have found the selective dopamine uptake blockers also significantly decrease oscillatory periods in basal ganglia firing rates, whereas the norepinephrine and serotonin uptake blockers have no significant effect. Current theories proposing that low doses of stimulants such as amphetamine and methylphenidate (Ritalin) reduce symptoms in attention deficit hyperactivity disorder patients by acting on dopamine autoreceptors to reduce catecholaminergic transmission have been contradicted by investigations of effects of these drugs on firing rates of basal ganglia neurons. The ability of these widely used therapies to dramatically alter periodicities of multisecond oscillations in basal ganglia activity support the view that catecholaminergic stimulants might affect motor and attentive processes by modulating temporal patterns of central activity. The relationship of these dopamine-modulated multisecond oscillations in basal ganglia activity to cerebrocortical activity and the possibility that thalamic neurons also express these slow oscillations has been assessed. The data show that multisecond oscillations in basal ganglia and thalamic neuronal firing rates have a correlate in variations in EEG theta power, an index of cortical activity associated with attention or arousal. Moreover, this correlation is strengthened by systemically-administered dopamine agonists, and agonist effects are enhanced after dopamine cell lesion in an animal model of Parkinson's disease. These investigations have also shown new parallels between the physiology of the rodent entopeduncular nucleus and its homolog in the primate, the internal segment of the globus pallidus. Impressive correlations between neurophysiological data from the rodent and primate models of Parkinson's disease and Parkinson's disease patients support the relevance of findings emerging from rodent studies with respect to basal ganglia function in humans and non-human primates.