Mizuno Takeo, Schmauss Claudia, Rayport Stephen
Department of Psychiatry, Columbia University, 1051 Riverside Drive, Unit 62, New York, NY 10032, USA.
BMC Neurosci. 2007 Jan 19;8:8. doi: 10.1186/1471-2202-8-8.
In both schizophrenia and addiction, pathological changes in dopamine release appear to induce alterations in the circuitry of the nucleus accumbens that affect coordinated thought and motivation. Dopamine acts principally on medium-spiny GABA neurons, which comprise 95% of accumbens neurons and give rise to the majority of inhibitory synapses in the nucleus. To examine dopamine action at single medium-spiny neuron synapses, we imaged Ca2+ levels in their presynaptic varicosities in the acute brain slice using two-photon microscopy.
Presynaptic Ca2+ rises were differentially modulated by dopamine. The D1/D5 selective agonist SKF81297 was exclusively facilitatory. The D2/D3 selective agonist quinpirole was predominantly inhibitory, but in some instances it was facilitatory. Studies using D2 and D3 receptor knockout mice revealed that quinpirole inhibition was either D2 or D3 receptor-mediated, while facilitation was mainly D3 receptor-mediated. Subsets of varicosities responded to both D1 and D2 agonists, showing that there was significant co-expression of these receptor families in single medium-spiny neurons. Neighboring presynaptic varicosities showed strikingly heterogeneous responses to DA agonists, suggesting that DA receptors may be differentially trafficked to individual varicosities on the same medium-spiny neuron axon.
Dopamine receptors are present on the presynaptic varicosities of medium-spiny neurons, where they potently control GABAergic synaptic transmission. While there is significant coexpression of D1 and D2 family dopamine receptors in individual neurons, at the subcellular level, these receptors appear to be heterogeneously distributed, potentially explaining the considerable controversy regarding dopamine action in the striatum, and in particular the degree of dopamine receptor segregation on these neurons. Assuming that post-receptor signaling is restricted to the microdomains of medium-spiny neuron varicosities, the heterogeneous distribution of dopamine receptors on individual varicosities is likely to encode patterns in striatal information processing.
在精神分裂症和成瘾中，多巴胺释放的病理变化似乎会导致伏隔核神经回路的改变，从而影响协调思维和动机。多巴胺主要作用于中等棘状γ-氨基丁酸（GABA）能神经元，这些神经元占伏隔核神经元的95%，并在伏隔核中形成了大部分抑制性突触。为了研究多巴胺在单个中等棘状神经元突触处的作用，我们使用双光子显微镜对急性脑片上其突触前膨体中的钙离子（Ca2+）水平进行了成像。
突触前Ca2+升高受到多巴胺的差异性调节。D1/D5选择性激动剂SKF81297只具有易化作用。D2/D3选择性激动剂喹吡罗主要起抑制作用，但在某些情况下也具有易化作用。使用D2和D3受体敲除小鼠的研究表明，喹吡罗的抑制作用是由D2或D3受体介导的，而其易化作用主要由D3受体介导。部分膨体对D1和D2激动剂均有反应，这表明这些受体家族在单个中等棘状神经元中存在显著的共表达。相邻的突触前膨体对多巴胺激动剂表现出明显的异质性反应，这表明多巴胺受体可能以不同方式转运到同一中等棘状神经元轴突上的各个膨体。
多巴胺受体存在于中等棘状神经元的突触前膨体上，在那里它们有力地控制着GABA能突触传递。虽然在单个神经元中D1和D2家族多巴胺受体存在显著的共表达，但在亚细胞水平上，这些受体似乎是异质性分布的，这可能解释了关于多巴胺在纹状体中作用的相当大的争议，特别是这些神经元上多巴胺受体的分离程度。假设受体后信号传导局限于中等棘状神经元膨体的微区，那么多巴胺受体在单个膨体上的异质性分布可能会编码纹状体信息处理中的模式。
