Role of mesopontine cholinergic afferents in methamphetamine reward

中脑桥胆碱能传入在甲基苯丙胺奖赏中的作用

• 批准号: 7911556
• 负责人: Lauren K Dobbs
• 金额: $ 4.14万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-26 至 2012-06-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911556
• 关键词: Abstinence; Acetylcholine; Affect; Area; Behavior; Behavioral; Characteristics; Cues; Dopamine; Dose; Environment; Exposure to; Extinction (Psychology); Goals; Measures; Mediating; Methamphetamine; Methamphetamine dependence; Microdialysis; Mus; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Phase; Relapse; Research; Rewards; Role; Self-Administered; Techniques; Training; Ventral Tegmental Area; cholinergic; cholinergic neuron; dopaminergic neuron; drug of abuse; effective therapy; laterodorsal tegmentum; neurochemistry; paired stimuli; public health relevance; research study; treatment strategy

DESCRIPTION (provided by applicant): Drug seeking and reward can be characterized by the burst firing of dopamine (DA) neurons in the ventral tegmental area (VTA) and increased DA release within the mesocorticolimbic pathway. Other neurotransmitters, such as acetylcholine (ACh), act in the VTA to increase DA release in an area of the pathway called the nucleus accumbens (NAc). ACh also mediates the behaviorally reinforcing characteristics of drugs of abuse. Our lab recently found that methamphetamine (MA) increases ACh and DA in VTA. The VTA primarily receives ACh connections from a mesopontine region known as the laterodorsal tegmentum (LDT) that when active can increase DA activity and induce release in other regions of the pathway. Thus, LDT cholinergic neurons may be involved in MA-induced increases in DA and ACh. Further, the intra-VTA ACh tone may mediate MA-seeking behaviors. The goals of this research involve isolating the ACh projection from the LDT to the VTA in order to determine its importance in the neurochemical (Specific Aim 1) and behavioral (Specific Aim 2) effects of MA in mice. The first aim will determine the involvement of the LDT ACh connection on MA-induced increases in ACh and DA. In this experiment I will reversibly inactivate the LDT ACh connection to the VTA and use microdialysis to measure DA and ACh in the VTA of mice. I anticipate that the inactivation of the LDT ACh will block MA-induced increases in ACh and DA in the VTA. The second aim will determine the involvement of the LDT ACh input to the VTA on reinstatement to MA-seeking. In this experiment I will train mice to self-administer MA and then extinguish this behavior. Typically after extinction a small priming dose of MA will reinstate MA- seeking behavior. Before this MA priming dose is administered I will reversibly inactivate the LDT ACh connection. I anticipate this inhibition of ACh will block MA-primed reinstatement to drug seeking. Persistent drug-seeking characteristic of MA addiction is maintained by the interactions of a wide neurochemical milieu within the mesocorticolimbic pathway. Although ACh has been found to be critically involved in reward and MA-related behaviors, the role of the LDT ACh projections to the VTA in MA-seeking behavior has yet to be characterized. This proposal combines neurochemical and behavioral approaches to define how this cholinergic projection affects the neurochemical environment within the VTA and ultimately affect MA-seeking. PUBLIC HEALTH RELEVANCE: A particularly vulnerable phase of methamphetamine addiction is following a period of abstinence when a priming dose of the drug or exposure to previously drug-paired stimuli (cues) can induce relapse. In order to develop more effective treatment strategies, it is important to understand the neurochemical underpinnings of reinstatement to methamphetamine-seeking behaviors. This proposal will use a combination of behavioral and neurochemical techniques to determine the neurochemical substrates that drive methamphetamine seeking.

描述（由申请人提供）：药物寻求和奖励可以通过腹侧被盖区（VTA）多巴胺（DA）神经元的突然放电和中皮质边缘通路内DA释放增加来表征。其他神经递质，如乙酰胆碱（ACh），在VTA中起作用，增加通路中一个叫做伏隔核（NAc）的区域的DA释放。乙酰胆碱还介导药物滥用的行为强化特征。我们的实验室最近发现甲基苯丙胺（MA）增加了VTA中的乙酰胆碱和乙酰胆碱。VTA主要从被称为侧背被（LDT）的中脑区接收ACh连接，当LDT活跃时，可以增加DA活性并诱导通路其他区域的释放。因此，LDT胆碱能神经元可能参与了ma诱导的DA和ACh的增加。此外，vta内ACh音可能介导ma寻求行为。本研究的目的包括分离乙酰胆碱从下dt到VTA的投射，以确定其在小鼠MA的神经化学（特异性目标1）和行为（特异性目标2）效应中的重要性。第一个目标是确定LDT乙酰胆碱连接在ma诱导的乙酰胆碱和乙酰胆碱增加中的作用。在这个实验中，我将可逆地失活LDT与VTA的ACh连接，并使用微透析测量小鼠VTA中的DA和ACh。我预计LDT乙酰胆碱的失活将阻断ma诱导的VTA乙酰胆碱和DA的增加。第二个目标将确定LDT ACh输入对恢复ma寻求的VTA的参与。在这个实验中，我将训练老鼠自我管理MA，然后熄灭这种行为。典型地，在消失后，小剂量的MA将恢复MA寻找行为。在给药之前，我将可逆地使LDT - ACh连接失活。我预计这种乙酰胆碱的抑制将阻止ma引发的药物寻找的恢复。MA成瘾的持续药物寻求特征是由中皮质边缘通路内广泛的神经化学环境的相互作用维持的。尽管已发现乙酰胆碱在奖励和ma相关行为中起关键作用，但LDT乙酰胆碱对VTA的投射在ma寻求行为中的作用尚未得到表征。该建议结合神经化学和行为方法来定义这种胆碱能投射如何影响VTA内的神经化学环境并最终影响ma寻找。