The Processing of Tonic and Burst Activity Patterns in DA Terminals in the NAcc

描述（由申请人提供）：相关性：许多滥用药物的成瘾倾向部分是通过激活大脑中称为中脑多巴胺通路的特定回路而产生的。本提案中描述的研究将确定阿片受体活性和钙通道抑制剂如何调节各种刺激模式释放的多巴胺。这项研究将促进我们对多巴胺通路的理解，并可能导致有效的成瘾治疗。项目摘要：纹状体中的多巴胺释放与许多大脑功能有关，包括运动控制、唤醒、注意力、动作选择、能量平衡以及学习和动机。负责这种释放的多巴胺能纤维在静止大鼠中表现出一致的紧张性放电模式。然而，在对行为相关刺激的反应中，这种基础活动被高频动作电位的短暂爆发打断。本提案中描述的实验评估了这些不同的放电模式实际释放的多巴胺的量如何在多巴胺轴突末梢中进行差异调节。这些研究将对药物成瘾研究领域做出重要贡献，因为许多滥用药物的成瘾倾向部分是通过提高纹状体中称为神经核的部分细胞外多巴胺浓度而产生的。对于许多药物，包括尼古丁和海洛因，这种效应是由于多巴胺神经元爆发放电模式的升级。快速扫描循环伏安法和安培法是电化学记录技术，可以实时检测多巴胺的阶段性释放。本实验将利用这些方法在大鼠脑片的中脑背外侧核中评估阿片受体活性和钙通道阻滞剂对低频和高频诱发的多巴胺释放的影响。该建议的第一个目的是利用特定的κ和μ阿片受体激动剂和拮抗剂，以确定阿片受体活性如何通过紧张性和爆发性刺激差异调节多巴胺释放。本提案的第二个目的将探索这些操作的潜在机制，并确定电压门控钙通道介导多巴胺释放的强直性和突发性刺激。这些研究将进一步加深我们对多巴胺释放动力学的理解，特别是关于多巴胺神经元所表现出的紧张性和爆发性放电模式。这项研究可能会导致有效的药物成瘾临床治疗。

DESCRIPTION (provided by applicant): Relevance: Many drugs of abuse derive their addiction liability, in part, by activating a specific circuit in the brain called the mesoaccumbens dopamine pathway. The research described in this proposal will determine how opioid receptor activity and calcium channel inhibitors can modulate the dopamine released by various stimulation patterns. This research will advance our understanding of the mesoaccumbens dopamine pathway and may lead to effective treatments for addiction. Project Summary: Dopamine release in the striatum is associated with many brain functions, including motor control, arousal, attention, action selection, energy balance, as well as learning and motivation. The dopaminergic fibers responsible for this release exhibit consistent, tonic firing patterns in quiescent rats. In response to behaviorally relevant stimuli, however, this basal activity is interrupted with brief bursts of high frequency action potentials. The experiments described in this proposal assess how the amount of dopamine actually released by these different firing patterns can be differentially modulated in the dopamine axon terminal. These investigations will make an essential contribution to the field of drug addiction research because many drugs of abuse derive their addiction liability, in part, by raising extracellular dopamine concentrations in a part of the striatum called the nucleus accumbens. For many drugs, including nicotine and heroin, this effect results from an escalation in dopamine neuron burst firing patterns. Fast-scan cyclic voltammetry and amperometry are electrochemical recording techniques that allow the detection of phasic dopamine release in real-time. The experiments in this proposal will utilized these methods in the nucleus accumbens of rat brain slices to assess the impact of both opioid receptor activity and calcium channel blockers on low and high frequency-evoked dopamine release. The first aim of this proposal will exploit specific kappa and mu opioid receptor agonists and antagonists to determine how opioid receptor activity differentially modulates dopamine release via tonic and burst stimuli. The second aim of this proposal will explore potential mechanisms for these manipulations and identify the voltage-gated calcium channels that mediate dopamine release in response to tonic and burst stimuli. These studies will further our understanding of dopamine release dynamics, specifically in regards to the tonic and burst firing patterns exhibited by dopamine neurons. This research may lead to effective clinical treatments for drug addiction.