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.

皮质和基底神经节中多巴胺释放的突触前可塑性与学习线索有关 引发可卡因自我给药，并通过过滤不显着的刺激来形成选择性注意。目标 该提案的目的是描述在神经元水平上介导突触前可塑性的机制 多巴胺能突触小泡胞吐作用。 我们最近报道，小的 DAergic 突触小泡的融合孔可以闪烁一次或多次 速度高达 10 kHz，从而调节囊泡释放的递质量。这提供了 目标 1 的基础，该目标询问如何调节融合孔的闪烁。 在嗜铬细胞中，我们发现囊泡酸化水平不是不变的，而是通过 细胞活动，可以增加量子大小。在这项提案中，我们展示了增强囊泡的证据 酸化可能是药物作用的基础（例如利他林），以及行为反馈改变的方法 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大小。 最后，我们确定了多种突触前受体如何在量子水平上改变 DA 传输 （例如，GDNF、D2、烟碱和 mGluR 激活）以及为什么这些因素对于 DA 作为社会性因素很重要 突触。大部分工作都是关于神经递质的急性影响。新证据表明持久 神经递质对 DA 传输的影响，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 DAergic 突触前静脉曲张的形成。