Physiology of midbrain dendritic dopamine transmission

描述(由申请人提供)： 腹侧中脑中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底物参与也就不足为奇了，例如药物成瘾、帕金森氏症、可能的精神分裂症和注意力缺陷多动障碍。多巴胺细胞通过投射到参与决策、运动和情绪的大脑区域来发挥其主要作用。少量的多巴胺也在中脑腹侧被盖区(VTA)和黑质(SN)的树状核附近释放。最近发现，这种树突状释放可能是通过逆转多巴胺转运蛋白发生的，多巴胺转运蛋白是一种广泛分布的膜结合蛋白，负责从细胞外空间自由摄取大部分多巴胺。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大脑远端区域的多巴胺释放。虽然VTA和SN中的多巴胺转运体和D2受体的存在提示了树突释放的生理作用，但确切的突触机制仍有待研究。这项建议通过研究动静脉管中树-树传递的机制来解决这一问题。全细胞膜片钳电生理技术将被用来记录大鼠中脑脑片中的多巴胺神经元。尤其令人感兴趣的是阐明代谢性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。苯丙胺，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了解树突释放多巴胺的重要性和作用。

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.