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

NAcc 中 DA 终端的强直和爆发活动模式的处理

• 批准号: 7442271
• 负责人: Jonathan Philip Britt
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-16 至 2009-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7442271
• 关键词: Action Potentials; Address; Affect; Agonist; Arousal; Attention; Behavior Disorders; Brain; Brain Diseases; Calcium Channel; Calcium Channel Blockers; Cholinergic Agents; Clinical Treatment; Condition; Corpus striatum structure; Detection; Disruption; Dopamine; Dopamine D2 Receptor; Drug Addiction; Exhibits; Fiber; Fire - disasters; Frequencies; Heroin; Investigation; Laboratories; Lead; Learning; Link; Measures; Mediating; Methods; Midbrain structure; Motivation; Neurons; Nicotine; Nicotinic Receptors; Nucleus Accumbens; Opioid Peptide; Opioid Receptor; Pathway interactions; Pattern; Pharmaceutical Preparations; Preparation; Presynaptic Terminals; Probability; Process; Property; Rattus; Research; Rewards; Rice; Role; Scanning; Series; Slice; Stimulus; System; Techniques; Testing; Time; addiction; cholinergic; concept; desensitization; dopaminergic neuron; drug of abuse; endogenous opioids; energy balance; extracellular; inhibitor/antagonist; kappa opioid receptors; motor control; mu opioid receptors; receptor; research study; response; voltage

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.

描述（由申请人提供）：相关性：许多滥用药物的成瘾责任部分通过激活大脑中的特定电路，称为中含多巴胺途径。该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通过各种刺激模式调节多巴胺。这项研究将促进我们对中核多巴胺途径的理解，并可能导致有效的成瘾治疗方法。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。负责此发行版的多巴胺能纤维在静止的大鼠中表现出一致的补品射击模式。然而，为了响应行为相关的刺激，这种基础活性被短暂的高频动作电位中断。本提案中描述的实验评估了这些不同的射击模式实际释放的多巴胺量如何在多巴胺轴突末端进行差异调节。这些研究将对药物成瘾研究领域做出重要贡献，因为许多滥用药物在某种程度上通过在称为Accumbens核的一部分中提高细胞外多巴胺浓度来导致其成瘾责任。对于包括尼古丁和海洛因在内的许多药物，这种影响是由于多巴胺神经元爆发模式的升级而产生的。快速扫描的循环伏安法和安培计量法是电化学记录技术，可实时检测阶段性多巴胺释放。该提案中的实验将在大鼠脑切片的伏隔核中利用这些方法来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。该提案的第一个目的是利用特定的Kappa和Mu阿片受体激动剂和拮抗剂来确定阿片类受体的活性如何通过补品和爆发刺激来差异地调节多巴胺释放。该提案的第二个目的将探索这些操纵的潜在机制，并确定电压门控钙通道，这些钙通道介导了响应于补品和爆发刺激的多巴胺释放的电压。这些研究将进一步了解多巴胺释放动力学，特别是关于多巴胺神经元表现出的滋补和爆发的发射模式。这项研究可能导致有效的药物成瘾临床治疗。