Physiology of midbrain dendritic dopamine transmission

描述（由申请人提供）： 中脑腹侧的多巴胺细胞在许多关键功能中发挥作用，包括运动过程，集中注意力，奖励和激励学习。因此，同样的细胞作为人类疾病的神经基质参与，如药物成瘾，帕金森病，以及可能的精神分裂症和注意力缺陷多动障碍，也就不足为奇了。多巴胺细胞通过向参与决策、运动和情绪的大脑区域投射来发挥其主要作用。少量多巴胺也在中脑腹侧被盖区（VTA）和黑质（SN）的中脑核附近以树突状方式释放。最近发现，这种树突状细胞的释放可能通过多巴胺转运蛋白的逆转而发生，多巴胺转运蛋白是一种广泛分布的膜结合蛋白，负责从细胞外空间摄取大部分游离多巴胺。通过这种机制释放的多巴胺可以激活多巴胺细胞体上的D2多巴胺受体，抑制放电，从而抑制与行为过程有关的远端大脑区域中多巴胺的释放。虽然存在多巴胺转运蛋白和D2受体的腹侧被盖区和SN表明树突状细胞释放的生理作用，精确的突触机制还有待研究。这项建议解决了这个问题，通过调查的机制dendredendritic传输中的腹侧被盖区。采用全细胞膜片钳电生理技术记录大鼠中脑脑片多巴胺能神经元。特别感兴趣的是代谢型谷氨酸受体在多巴胺诱导的多巴胺细胞放电抑制中的作用的阐明。安非他明，一种已知作用于多巴胺能细胞的滥用药物，也将被用来试图获得和理解多巴胺树突状细胞释放的重要性和作用。

DESCRIPTION (provided by applicant): Dopamine cells in the ventral midbrain serve a role in a number of critical functions, including motor processes, focused attention, reward and incentive learning. It is not surprising then that the same cells participate as neural substrates of human diseases such as drug addiction, Parkinson's disease, and likely schizophrenia and attention deficit hyperactivity disorder. Dopamine cells exert their main effects distally through projections to brain regions involved in decision making, movement, and emotion. Small amounts of dopamine are also released dendritically near the midbrain nuclei of the ventral tegmental area (VTA) and substantia nigra (SN). Recently it was discovered that this dendritic release may occur through reversal of the dopamine transporter, a widely-distributed membrane-bound protein responsible for the majority of free dopamine uptake from the extracellular space. Dopamine released by this mechanism can activate D2 dopamine receptors on the dopamine cell bodies, inhibiting firing, and thus the release of dopamine in distal brain regions implicated in behavioral processes. While the existence of dopamine transporters and D2 receptors in the VTA and SN suggest a physiological role for dendritic release, the precise synaptic mechanisms have yet to be investigated. This proposal addresses this issue by investigating the mechanisms of dendrodendritic transmission in the VTA. Whole-cell patch clamp electrophysiological technique will be used to record from dopamine neurons in rat midbrain slices. Of particular interest is the elucidation of the role of metabotropic glutamate receptors in the dopamine-induced inhibition of dopamine cell firing. Amphetamine, a drug of abuse known to act on dopaminergic cells, will also be used to attempt to gain and understanding of the importance and role of the dendritic release of dopamine.