Stress-Induced Alterations in Amygdala-LC Interactions

压力引起的杏仁核-LC 相互作用的改变

• 批准号: 7645265
• 负责人: ANTHONY A GRACE
• 金额: $ 32.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645265
• 关键词: Acute; Affect; Alcoholism; Amphetamines; Amygdaloid structure; Animal Testing; Animals; Area; Behavior; Behavioral; Brain; Chronic; Chronic stress; Data; Development; Disease; Dopamine; Drug Sensitization; Drug abuse; Event; Funding; Hippocampus (Brain); Human; Individual; Lead; Lesion; Limbic System; Link; Measures; Mediating; Mental disorders; Microdialysis; Modeling; Neurobiology; Neurons; Neurotransmitters; Norepinephrine; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Play; Population; Population Control; Process; Property; Rattus; Relapse; Rewards; Role; Site; Stimulus; Stress; Structure; Symptoms; System; Testing; Therapeutic Intervention; Treatment Protocols; Work; behavioral sensitization; craving; dopamine system; dopaminergic neuron; drug seeking behavior; in vivo; insight; locus ceruleus structure; memory process; nerve supply; norepinephrine system; novel; psychostimulant; research study; response; restraint; restraint stress; stressor; transmission process

DESCRIPTION (provided by applicant): Stress is a major factor in the onset and relapse to drug abuse. Over the past funding period, the effects of stress on the amygdala-locus coeruleus (LC) system, and how the response is altered after chronic stress exposure, was examined. In this resubmission, this will be extended to systems affected by the LC, and how they may impact drug abuse. Stress and drug abuse share a number of features in common, including the ability to release dopamine (DA) and norepinephrine (NE) in target structures, and a strong association with context. For this reason, this work focuses on one area in particular: the ventral subiculum (vSub) of the hippocampus. The vSub is centrally involved in context dependent processes, and increasing evidence points to its crucial role in regulating stress responsivity. Furthermore, we have shown that the vSub exerts potent control over DA neuron activity by controlling the population activity (i.e., proportion of DA neurons firing spontaneously), which sets the "gain" of the system when it responds to phasic events. Our preliminary data suggest that vSub-induced activation of DA neuron population activity may underlie behavioral sensitization to amphetamine. Thus, sensitization to amphetamine by stress or by repeated treatment leads to an increase in DA neuron population activity that can be circumvented by inactivation of the vSub. Moreover, both the amygdala and the NE system provide a strong activation of vSub neuron firing. Our central hypothesis is that both amphetamine treatment and stress exert a common action, i.e., vSub-mediated activation of DA neuron population activity, which underlies drug sensitization. We will pursue this using in vivo recordings in the vSub and from ventral tegmental DA neurons, using behavioral and microdialysis measures to confirm sensitized responses. We will explore this along the following specific aims: 1) Examine whether acute stressors or noxious stimuli activate the vSub, and whether this is dependent on NE and BLA afferents; this will show if stimuli known to lead to sensitization also activate the vSub. 2) Examine the effects of acute stressors on DA neuron activity and behavioral response to amphetamine, and if this is mediated via the vSub; this will evaluate the role of the vSub in stress-induced increase in DA neuron population activity. 3) Examine the effects of acute versus repeated amphetamine on DA neuron activity; this will evaluate whether increased DA neuron population firing as driven by the vSub also contributes to amphetamine-induced sensitization. 4) Examine how chronic stress alters DA neuron firing and amphetamine sensitization; this will extend our previous results on alterations in the amygdala-NE system during chronic stress, and how this impacts sensitization. The role of sensitization in drug taking is not clear; however, substantial data suggest that psychostimulant sensitization plays a central role in craving and relapse to drug-taking behavior. By gaining a better understanding of the neurobiological consequences of stress exposure, we hope to uncover the neuroadaptive changes that take place within the limbic system that predispose an individual to drug-taking behavior and contribute to relapse. Stress plays a major role in the propensity of humans to engage in drug-taking behavior and to suffer relapse, and is known to increase the rewarding properties of drugs such as amphetamine in animals. Both stress and amphetamine have common actions on the neurotransmitter dopamine in the brain. In this project, we test for common adaptive changes that are produced in a brain exposed to amphetamine and stress in order to better understand what causes people to become addicted and relapse to drug taking behavior, and to guide development of more effective long-term treatments for drug abuse.

描述（由申请人提供）：压力是发作和滥用药物滥用的主要因素。在过去的资金期间，应检查应力对杏仁核二核（LC）系统的影响，以及如何检查慢性应激暴露后的反应如何改变。在此重新提交中，这将扩展到受LC影响的系统，以及它们如何影响滥用药物。压力和药物滥用具有许多共同的特征，包括在目标结构中释放多巴胺（DA）和去甲肾上腺素（NE）的能力，以及与环境的牢固关联。因此，这项工作尤其关注一个区域：海马的腹侧下膜（VSUB）。 VSUB集中参与上下文依赖过程，而增加证据表明其在调节压力反应性中的关键作用。此外，我们已经表明，VSUB通过控制人口活动（即自发发射的DA神经元的比例）对DA神经元活性产生有效的控制，从而在对质量事件做出响应时设定了系统的“增益”。我们的初步数据表明，VSUB诱导的DA神经元种群活性的激活可能是对苯丙胺的行为敏感性的基础。因此，通过压力或反复治疗对苯丙胺的敏化导致DA神经元种群活性的增加，可以通过VSUB失活来规避。此外，杏仁核和NE系统都提供了VSUB神经元射击的强大激活。我们的中心假设是，苯丙胺治疗和压力都具有共同的作用，即VSUB介导的DA神经元种群活性的激活，这是药物敏化的基础。我们将使用VSUB中的体内记录和腹侧对接DA神经元进行此类录制，并使用行为和微透析措施来确认敏化反应。我们将按照以下特定目的探讨这一点：1）检查急性应激源或有害刺激是否激活VSUB，以及这是否取决于NE和BLA传入；这将表明是否已知导致敏化的刺激也激活了VSUB。 2）检查急性应激源对苯丙胺的DA神经元活性和行为反应的影响，如果这是通过VSUB介导的；这将评估VSUB在压力诱导的DA神经元种群活性增加中的作用。 3）检查急性与重复苯丙胺对DA神经元活性的影响；这将评估VSUB驱动的DA神经元人群的增加是否也有助于苯丙胺诱导的敏化。 4）检查慢性应激如何改变DA神经元的发射和苯丙胺敏感性；这将扩大我们先前关于在慢性压力期间杏仁核系统改变的结果，以及这如何影响致敏。敏化在药物服用中的作用尚不清楚。但是，大量数据表明，精神刺激性敏化在渴望和对吸毒行为的复发中起着核心作用。通过更好地了解压力暴露的神经生物学后果，我们希望揭示边缘系统中发生的神经适应性变化，这些变化使人倾向于吸毒行为并有助于复发。压力在人类参与吸毒行为和遭受复发的倾向中起着重要作用，并且已知会增加动物中苯丙胺等药物的奖励性能。压力和苯丙胺对大脑中神经递质多巴胺都有共同的作用。在该项目中，我们测试了暴露于苯丙胺和压力的大脑中产生的常见自适应变化，以便更好地了解是什么导致人们上瘾并复发到吸毒行为，并指导对药物滥用的更有效的长期治疗。