Cragg S J, Hille C J, Greenfield S A
University Department of Pharmacology, Oxford, OX1 3QT, United Kingdom.
J Neurosci. 2000 Nov 1;20(21):8209-17. doi: 10.1523/JNEUROSCI.20-21-08209.2000.
The putamen of the human striatum is a heterogeneous nucleus that contains the primary site of loss of dopamine (DA) in Parkinson's disease (PD). Furthermore, different functional domains of the putamen are heterogeneously susceptible to DA loss, and yet the dynamic regulation of extracellular DA concentration (DA) and comparison between domains has not been explored in the primate brain. In these studies, DA was measured in real time using fast-scan cyclic voltammetry at a carbon-fiber microelectrode in vitro in striatal sections from the common marmoset (Callithrix jacchus). DA released by a single stimulus pulse varied threefold along a ventromedial-dorsolateral axis. DA uptake was via the DA transporter (GBR12909 sensitive, desipramine insensitive). On the basis of data modeling with simulations of Michaelis-Menten kinetics, rate maximum, V(max), varied with region: both DA and V(max) were greatest in regions most vulnerable in PD. These differences were reflected in part by regional variation in DA content. DA, V(max), and regional variation were two- to threefold greater than in rodent caudatoputamen. In addition, steady-state DA at physiological firing rates in primate striatum was controlled by depolarization frequency, uptake, and presynaptic autoreceptors. Furthermore, regulation of DA by these mechanisms differed significantly between limbic- and motor-associated domains. These data indicate interspecies heterogeneity in striatal DA dynamics that must be considered when extrapolating behavioral and drug responses from rodent to the primate brain. Moreover, the heterogeneity demonstrated within the primate putamen in the availability and dynamic regulation of DA may be central to understanding DA function in health, cocaine abuse, and disease.
人类纹状体的壳核是一个异质性核团，是帕金森病（PD）中多巴胺（DA）丧失的主要部位。此外，壳核的不同功能域对DA丧失的易感性各不相同，然而，灵长类动物大脑中细胞外DA浓度（DA）的动态调节以及不同功能域之间的比较尚未得到研究。在这些研究中，使用快速扫描循环伏安法在体外对普通狨猴（Callithrix jacchus）纹状体切片中的碳纤维微电极进行实时DA测量。单个刺激脉冲释放的DA沿腹内侧 - 背外侧轴变化了三倍。DA摄取是通过DA转运体（对GBR12909敏感，对去甲丙咪嗪不敏感）进行的。基于用米氏动力学模拟进行的数据建模，最大速率V(max)随区域而变化：DA和V(max)在PD中最易受损的区域最大。这些差异部分反映在DA含量的区域变化上。DA、V(max)和区域变化比啮齿动物的尾壳核大两到三倍。此外，灵长类动物纹状体在生理放电频率下的稳态DA受去极化频率、摄取和突触前自身受体的控制。此外，这些机制对DA的调节在边缘相关域和运动相关域之间存在显著差异。这些数据表明纹状体DA动力学存在种间异质性，在从啮齿动物推断到灵长类动物大脑的行为和药物反应时必须予以考虑。此外，灵长类动物壳核内DA可用性和动态调节中表现出的异质性可能是理解DA在健康、可卡因滥用和疾病中的功能的核心。
