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

• 批准号: 10306376
• 负责人: LYNN G KIRBY
• 金额: $ 35.66万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306376
• 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

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，并且与更大的脆弱性有关 药物服用，从药物使用到滥用的更快过渡以及较高的药物复发率，尽管神经 涉及的电路和机制在很大程度上未知。越来越多的文献表明 某些情感的背侧raphe核（DRN） - 苏罗替辛（5-羟色胺; 5-HT）系统 吸毒成瘾的成分，可以激发药物服用和复发。急性阿片类药物刺激5-HT 通过GABA能抑制神经传递，有可能促成积极的情感成分 在阿片类药物成瘾早期寻求药物的动机。相比之下，后来成瘾，5-HT DRN系统可能 还通过对压力及其压力及其的反应能力进行负面影响而导致寻求毒品的寻求毒品 与皮质激素释放因子（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。初步数据表明了一种新颖 DRN-CRF电路中的神经适应与应激诱导的阿片类药物复发有关。 表示海洛因静脉自我给药（IVSA）或吗啡条件的大鼠 暴露于压力的场所优先（CPP）恢复了以前灭绝的海洛因寻求 行为或吗啡CPP，伴随着GABAA受体对5-HT DRN神经元的敏感性。 这种神经适应将使5-HT DRN神经元容易受到CRF-R1-GABA输入的抑制作用。从 这些集体数据，我们假设阿片类药物成瘾中5-HT系统的双重作用：1）早期阿片类药物 暴露会刺激5-HT DRN神经元，从而产生积极的情感状态，从而有助于阿片类药物奖励； 2） 阿片类药物史的受试者的压力暴露使5-HT DRN神经元上的GABAA受体敏感 它们容易受到GABA传入中CRF-R1的抑制作用。由此产生的5-HT功能功能会产生 消极的情感状态，激励阿片类药物恢复原状。在特定目标1中，我们将使用电生理学 测量膜特性的动态变化以及5-HT DRN神经元的兴奋性在体内的兴奋性 在海洛因IVSA，灭绝和压力的大鼠模型过程中，情感和行为的变化跟踪 - 诱导的恢复原状。在特定目标2中，我们将使用专门激活的设计器受体的病毒输送 由TPH2-CRE大鼠中的设计师药物检查处理5-HT DRN神经元活动的影响 在行为模型中。在特定目标3中，我们将使用CRH-CRE或GAD-CRE大鼠的Dreadds的病毒传递到 测试杏仁核CRF传入与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 在阿片类药物成瘾模型中的GABA-CRF电路和复发的最终目标是识别新颖的目标 治疗阿片类药物成瘾并防止复发的治疗靶标。