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; 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）：寻求和奖励的特征是在腹侧段区域（VTA）（VTA）中爆发多巴胺（DA）神经元的爆发，并增加了中皮质胶质途径内的DA释放。其他神经递质（例如乙酰胆碱（ACH））在VTA中起作用，以增加称为伏隔核（NAC）的途径区域中DA释放。 ACH还调解了滥用药物的行为加强特征。我们的实验室最近发现，甲基苯丙胺（MA）在VTA中增加了ACH和DA。 VTA主要接收来自被称为Laterodorsal temgentum（LDT）的中桥区域的ACH连接，当活性时可以增加DA活性并诱导途径其他区域的释放。因此，LDT胆碱能神经元可能与DA和ACH的MA诱导的增加有关。此外，VTA ACH内音可能会介导寻求MA的行为。 这项研究的目标涉及隔离LDT到VTA的ACH投影，以确定其在神经化学（特定目标1）和MA对MA在小鼠中的行为（特定目标2）效应的重要性。第一个目标将确定LDT ACH连接在MA诱导的ACH和DA增加中的参与。在此实验中，我将不动将LDT ACH连接与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的失活会阻止MA诱导的VTA中ACH和DA的增加。 第二个目标将确定LDT ACH输入恢复到Ma-seeking时的参与。在这项实验中，我将训练小鼠自我管理的MA，然后消除这种行为。通常，在灭绝后，小启动剂量的MA将恢复降低的行为。在给予MA启动剂量之前，我将不动活地使LDT ACH连接失活。我预计这种对ACH的抑制作用将阻止MA培养的恢复原状。 MA成瘾的持续寻求药物的特征是通过中性胶质途径中广泛的神经化学环境的相互作用来维持的。尽管已经发现ACH与奖励和与MA相关的行为非常重要，但LDT ACH对VTA在MA寻求行为中的作用尚待表征。该建议结合了神经化学和行为方法，以定义该胆碱能投射如何影响VTA内的神经化学环境，并最终影响MA-Seeking。 公共卫生相关性：甲基苯丙胺成瘾的一个特别脆弱的阶段是在禁欲之后，当时药物的启动剂量或暴露于以前的药物配对刺激（提示）可以引起复发。为了制定更有效的治疗策略，重要的是要了解恢复到寻求甲基苯丙胺行为的神经化学基础。该建议将结合行为和神经化学技术来确定驱动甲基苯丙胺寻求的神经化学底物。