PRESYNAPTIC PLASTICITY OF VESICULAR DOPAMINE RELEASE

囊泡多巴胺释放的突触前可塑性

• 批准号: 7088089
• 负责人: David Sulzer
• 金额: $ 16.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088089
• 关键词: attention; basal ganglia; behavior; central nervous system stimulants; chromaffin cells; cocaine; cues; density; dopamine; exocytosis; fasting; learning; methylphenidate; neurotransmitters; pharmacokinetics; receptor; synapses; synaptic vesicles

Presynaptic plasticity of dopamine release in the cortex and basal ganglia is involved in learning cues that elicit cocaine self-administration and underlie selective attention by filtering non-salient stimuli. The objective of this proposal is to characterize mechanisms that mediate presynaptic plasticity at the level of the dopaminergic synaptic vesicle exocytosis. We recently reported that the fusion pores of small DAergic synaptic vesicles can flicker once or multiple times as fast as 10 kHz, thus regulating the amount of transmitter released from a vesicle. This provides the basis for Aim 1, which asks how flickering of fusion pores is regulated. In chromaffin cells, we discovered that the level of vesicle acidification is not invariant but enhanced by cellular activity, which can increase quantal size. In this proposal, we show evidence for enhanced vesicular acidification that may underlie drug actions (e.g., Ritalin), and a means for behavior to feed back to alter long-term transmission. This provides the basis for Aim 2 explores whether psychostimulants regulate quantal size via rebound of vesicular acidification. Finally, we identified how a variety of presynaptic receptors alter DA transmission at the quantal level (e.g., GDNF, D2, nicotinic, and mGluR activation) and why these factors are important for DA as social synapses. Most of the work has been on acute effects of neurotransmitters. New evidence indicates long-lasting effects of neurotransmitters on DA transmission, particularly on the density/formation of axonal presynaptic varicosities. Accordingly, Aim 3 will examine how neurotransmitters regulate DAergic presynaptic varicosity formation.

皮层和基底神经节中多巴胺释放的突触前可塑性参与学习线索， 引起可卡因自我管理和过滤非显着刺激的选择性注意的基础。客观 这一建议的特点是机制，介导突触前可塑性的水平， 多巴胺能突触囊泡胞吐作用。 我们最近报道，DA能突触小泡的融合孔可以闪烁一次或多次， 其速度是10 kHz的两倍，从而调节从囊泡释放的递质的量。这提供了以下 目标1的基础，其询问融合孔的闪烁是如何调节的。 在嗜铬细胞中，我们发现囊泡酸化的水平不是不变的，而是通过 细胞活动，这可以增加量子大小。在这个提议中，我们显示了增强的囊泡 可能是药物作用基础的酸化（例如，利他林），以及一种行为反馈以改变 长期传播。这为目标2探索精神兴奋剂是否调节 通过囊泡酸化的反弹来改变量子尺寸。 最后，我们确定了各种突触前受体如何在量子水平上改变DA的传递 (e.g., GDNF，D2，烟碱和mGluR激活）以及为什么这些因素对DA作为社会性 突触大部分的工作都是关于神经递质的急性效应。新的证据表明 神经递质对DA传递的影响，特别是对轴突密度/形成的影响 突触前静脉曲张因此，目标3将研究神经递质如何调节DA能 突触前静脉曲张形成