Regulation of 5-HT circuits by CRF and GABA in opioid addiction and stress-induced relapse

CRF 和 GABA 对阿片类药物成瘾和应激性复发中 5-HT 回路的调节

基本信息

批准号：
10556667
负责人：
LYNN G KIRBY
金额：
$ 15.85万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10556667
关键词：
Acute Affect Affective Amygdaloid structure Animal Model Behavior Behavioral Behavioral Model Cell Nucleus Corticotropin-Releasing Hormone Coupled Data Designer Drugs Disinhibition Drug Addiction Drug usage Electrophysiology (science)Exposure to Extinction (Psychology)Genetic Recombination Goals Heroin Human Interneurons Intravenous Laboratories Ligands Literature Measures Membrane Modeling Morphine Motivation Neurobiology Neurohormones Neurons Opiate Addiction Opioid Output Pathway interactions Pharmaceutical Preparations Pharmacology Phase Process Property Public Health Rattus Recording of previous events Regulation Relapse Rewards Role Self Administration Serotonergic System Serotonin Signal Transduction Slice Stress System Techniques Testing Transgenic Organisms Ultrasonics Viral addiction behavioral response conditioned place preference designer receptors exclusively activated by designer drugs disorder later incidence prevention dorsal raphe nucleus drug relapse drug seeking behavior drug withdrawal gamma-Aminobutyric Acid in vivo indexing negative affect neural circuit neuroadaptation neuromechanism neurotransmission new therapeutic target novel opioid exposure prevent receptor stressor theories tool vocalization

项目摘要

Stress impacts multiple phases of opioid addiction and is associated with greater vulnerability to initiation of drug taking, more rapid transition from drug use to abuse, and higher rates of drug relapse, though the neural circuitry and mechanisms involved are largely unknown. A growing literature indicates the involvement of the dorsal raphe nucleus (DRN)-serotonin (5-hydroxytryptamine; 5-HT) system in some of the affective components of drug addiction that motivate drug taking and relapse. Acute opioids stimulate 5-HT neurotransmission via GABAergic disinhibition, potentially contributing a positive affective component to the motivation for drug seeking early in opioid addiction. By contrast, later in addiction, the 5-HT DRN system may also contribute to drug-seeking motivated by negative affect via its responsiveness to stressors and its interaction with the corticotropin-releasing factor (CRF) system. Our laboratory and others have shown that CRF-R1 receptors inhibit 5-HT DRN neurons via GABA interneurons. Preliminary data indicate a novel neuroadaptation within DRN-CRF circuits that is associated with vulnerability to stress-induced opioid relapse. Rats expressing extinction of either heroin intravenous self-administration (IVSA) or morphine conditioned place-preference (CPP) that are exposed to stress reinstate their previously extinguished heroin-seeking behavior or morphine CPP, an effect accompanied by sensitization of GABAA receptors on 5-HT DRN neurons. This neuroadaptation would render 5-HT DRN neurons vulnerable to inhibition by CRF-R1-GABA inputs. From these collective data, we hypothesize a dual role for the 5-HT system in opioid addiction: 1) early opioid exposure stimulates 5-HT DRN neurons, creating a positive affective state that contributes to opioid reward; 2) stress exposure in subjects with an opioid history sensitizes GABAA receptors on 5-HT DRN neurons, making them vulnerable to inhibition by CRF-R1 located on GABA afferents. The resulting 5-HT hypofunction creates a negative affective state that motivates opioid reinstatement. In specific aim 1, we will use electrophysiology to measure the dynamic changes in membrane properties and excitability of 5-HT DRN neurons ex vivo as they track with changes in affect and behavior over the course of a rat model of heroin IVSA, extinction and stress- induced reinstatement. In specific aim 2 we will use viral delivery of Designer Receptor Exclusively Activated by Designer Drugs in Tph2-Cre rats to examine the impact of manipulating 5-HT DRN neuronal activity in vivo in the behavioral model. In specific aim 3 we will use viral delivery of DREADDs in Crh-Cre or GAD-Cre rats to test the causal relationship between amygdala CRF afferents to the DRN and DRN GABA interneurons in the behavioral model. This proposal employs multiple ex vivo and in vivo approaches to dissect the role of 5-HT- GABA-CRF circuitry in a model of opioid addiction and relapse with the ultimate goal of identifying novel therapeutic targets to treat opioid addiction and prevent relapse.

压力会影响阿片类药物成瘾的多个阶段，并且与更容易开始阿片类药物成瘾有关吸毒、从吸毒到滥用的更快转变以及吸毒复吸率更高，尽管神经所涉及的电路和机制在很大程度上是未知的。越来越多的文献表明，中缝背核（DRN）-血清素（5-羟色胺；5-HT）系统在一些情感促使吸毒和复吸的毒瘾成分。急性阿片类药物刺激 5-HT 通过 GABA 能去抑制进行神经传递，可能有助于积极的情感成分阿片类药物成瘾早期寻求药物的动机。相比之下，在成瘾后期，5-HT DRN 系统可能会还通过对压力源的反应及其对负面情绪的反应，导致寻求药物的动机与促肾上腺皮质激素释放因子（CRF）系统的相互作用。我们的实验室和其他实验室已经表明 CRF-R1 受体通过 GABA 中间神经元抑制 5-HT DRN 神经元。初步数据显示新颖 DRN-CRF 回路内的神经适应与压力诱导的阿片类药物复发的脆弱性相关。大鼠表现出海洛因静脉自我给药（IVSA）或吗啡条件消失暴露在压力下的地方偏好（CPP）会恢复之前熄灭的海洛因寻求行为或吗啡 CPP，这种效应伴随着 5-HT DRN 神经元上 GABAA 受体的敏化。这种神经适应会使 5-HT DRN 神经元容易受到 CRF-R1-GABA 输入的抑制。从根据这些集体数据，我们假设 5-HT 系统在阿片类药物成瘾中具有双重作用：1）早期阿片类药物暴露会刺激 5-HT DRN 神经元，产生积极的情感状态，有助于阿片类药物奖励； 2）有阿片类药物使用史的受试者的压力暴露会使 5-HT DRN 神经元上的 GABAA 受体敏感，从而它们容易受到位于 GABA 传入神经上的 CRF-R1 的抑制。由此产生的 5-HT 功能减退会产生促使阿片类药物恢复的负面情感状态。在具体目标 1 中，我们将利用电生理学来离体测量 5-HT DRN 神经元膜特性和兴奋性的动态变化跟踪海洛因 IVSA 大鼠模型、灭绝和压力过程中情感和行为的变化诱导恢复。在具体目标 2 中，我们将使用独家激活的设计受体的病毒传递通过 Designer Drugs 在 Tph2-Cre 大鼠中检查体内操纵 5-HT DRN 神经元活动的影响在行为模型中。在具体目标 3 中，我们将在 Crh-Cre 或 GAD-Cre 大鼠中使用 DREADD 的病毒递送来测试杏仁核 CRF 传入 DRN 和 DRN GABA 中间神经元之间的因果关系行为模型。该提案采用多种离体和体内方法来剖析 5-HT- 的作用阿片类药物成瘾和复发模型中的 GABA-CRF 电路，最终目标是识别新型药物治疗目标是治疗阿片类药物成瘾并防止复发。