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: 8101254
• 负责人: Lauren K Dobbs
• 金额: $ 4.18万
• 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/8101254
• 关键词: Abstinence; Acetylcholine; Address; Affect; Area; Attenuated; Behavior; Behavioral; Cells; Characteristics; Cues; Dopamine; Dose; Environment; Exposure to; Extinction (Psychology); Goals; Injection of therapeutic agent; Intravenous; Measures; Mediating; Methamphetamine; Methamphetamine dependence; Microdialysis; Microinjections; Mus; Muscarinic Agonists; Muscarinic M2 Receptor; Neurotransmitters; Nucleus Accumbens; Oxotremorine; Pathway interactions; Pharmaceutical Preparations; Phase; Relapse; Research; Research Training; Rewards; Role; Self-Administered; Techniques; Testing; Training; Ventral Tegmental Area; cholinergic; cholinergic neuron; dopaminergic neuron; drug of abuse; effective therapy; extracellular; laterodorsal tegmentum; neurochemistry; neuronal cell body; paired stimuli; research study; treatment strategy

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.

药物寻求和奖励的特点是腹侧被盖区 (VTA) 多巴胺 (DA) 神经元的爆发性放电以及中皮质边缘通路内 DA 释放的增加。其他神经递质，如乙酰胆碱 (ACh)，在 VTA 中发挥作用，增加伏隔核 (NAc) 通路区域中 DA 的释放。乙酰胆碱还介导滥用药物的行为强化特征。我们的实验室最近发现甲基苯丙胺 (MA) 会增加 VTA 中的 ACh 和 DA。 VTA 主要接收来自称为后背被盖 (LDT) 的中脑桥区域的 ACh 连接，当该区域活跃时可以增加 DA 活性并诱导该通路其他区域的释放。因此，LDT 胆碱能神经元可能参与 MA 诱导的 DA 和 ACh 增加。此外，VTA 内 ACh 音调可能介导 MA 寻求行为。 本研究的目标包括分离从 LDT 到 VTA 的 ACh 投射，以确定其在小鼠 MA 的神经化学（具体目标 1）和行为（具体目标 2）影响中的重要性。第一个目标是确定 LDT ACh 连接对 MA 诱导的 ACh 和 DA 增加的影响。在本实验中，我将可逆地灭活 LDT ACh 与 VTA 的连接，并使用微透析来测量小鼠 VTA 中的 DA 和 ACh。我预计 LDT ACh 失活将阻止 MA 诱导的 VTA 中 ACh 和 DA 的增加。 第二个目标将确定 LDT ACh 输入对 VTA 的参与，以恢复 MA 寻求。在这个实验中，我将训练小鼠自我管理 MA，然后消除这种行为。通常，在灭绝后，小剂量的 MA 将恢复寻找 MA 的行为。在给予 MA 启动剂量之前，我将可逆地灭活 LDT ACh 连接。我预计这种对 ACh 的抑制将阻止 MA 引发的药物寻求恢复。 MA 成瘾的持续药物寻求特征是通过中皮质边缘通路内广泛的神经化学环境的相互作用来维持的。尽管 ACh 已被发现与奖励和 MA 相关行为密切相关，但 LDT ACh 投射到 VTA 在 MA 寻求行为中的作用尚未得到表征。该提案结合了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 寻求。