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）：压力是药物滥用发生和复发的主要因素。在过去的资助期间，研究人员检查了压力对杏仁核蓝斑（LC）系统的影响，以及慢性压力暴露后反应如何改变。在这次重新提交中，这将扩展到受 LC 影响的系统，以及它们如何影响药物滥用。压力和药物滥用有许多共同特征，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，以及与环境的强烈关联。因此，这项工作特别关注一个区域：海马体的腹侧下托（vSub）。 vSub 主要参与环境相关过程，越来越多的证据表明它在调节压力反应性方面发挥着至关重要的作用。此外，我们还表明，vSub 通过控制群体活动（即自发放电的 DA 神经元比例）来对 DA 神经元活动进行有效控制，这会在系统响应阶段性事件时设置系统的“增益”。我们的初步数据表明，vSub 诱导的 DA 神经元群活动激活可能是对安非他明行为敏感的基础。因此，压力或重复治疗对安非他明的敏感性会导致 DA 神经元群活性的增加，这可以通过 vSub 的失活来避免。此外，杏仁核和 NE 系统都提供 vSub 神经元放电的强烈激活。我们的中心假设是安非他明治疗和压力都会发挥共同作用，即 vSub 介导的 DA 神经元群活动激活，这是药物敏化的基础。我们将利用 vSub 和腹侧被盖 DA 神经元的体内记录来实现这一目标，并使用行为和微透析措施来确认敏化反应。我们将沿着以下具体目标进行探索：1）检查急性应激源或有害刺激是否激活vSub，以及这是否依赖于NE和BLA传入；这将显示已知会导致敏化的刺激是否也会激活 vSub。 2) 检查急性应激源对 DA 神经元活动和对安非他明的行为反应的影响，以及这是否是通过 vSub 介导的；这将评估 vSub 在压力诱导的 DA 神经元群活动增加中的作用。 3) 检查急性与重复使用安非他明对 DA 神经元活性的影响；这将评估 vSub 驱动的 DA 神经元群放电增加是否也有助于安非他明诱导的敏化。 4) 检查慢性压力如何改变 DA 神经元放电和安非他明敏化；这将扩展我们之前关于慢性压力期间杏仁核-NE 系统变化及其如何影响敏化的结果。致敏作用在吸毒过程中的作用尚不清楚；然而，大量数据表明，精神兴奋剂致敏在吸毒行为的渴望和复发中发挥着核心作用。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内发生的神经适应性变化，这些变化使个体容易出现吸毒行为并导致复发。压力在人类吸毒行为和复吸的倾向中起着重要作用，并且众所周知，压力会增加动物中苯丙胺等药物的奖励特性。压力和安非他明对大脑中的神经递质多巴胺有共同的作用。在这个项目中，我们测试了暴露于安非他明和压力的大脑中产生的常见适应性变化，以便更好地了解导致人们上瘾和吸毒行为复发的原因，并指导开发更有效的长期治疗方法滥用药物。