GABAergic Sensitization of the Serotonin System in Stress-Induced Opiate Relapse

应激性阿片类药物复吸中血清素系统的 GABA 能敏化

• 批准号: 8682456
• 负责人: LYNN G KIRBY
• 金额: $ 23.36万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682456
• 关键词: Abstinence; Analgesics; Animal Model; Animals; Behavioral; Cells; Corticotropin-Releasing Hormone; Data; Electrophysiology (science); Engineering; Exploratory/Developmental Grant; Genes; Genetic; Genetic Recombination; Health; Immunohistochemistry; Laboratories; Modeling; Moods; Morphine; Morphine Dependence; Mus; Neurobiology; Neurohormones; Neurons; Opiate Addiction; Opiates; Opioid; Pathway interactions; Public Health; Quantitative Autoradiography; Recording of previous events; Regulation; Relapse; Reporter; Resistance; Rewards; Rodent; Role; Self Administration; Serotonin; Signal Transduction; Stress; Swimming; System; Tamoxifen; Testing; Viral; Work; base; biological adaptation to stress; disorder later incidence prevention; dorsal raphe nucleus; drug seeking behavior; gamma-Aminobutyric Acid; innovation; novel; preference; promoter; raphe nuclei; receptor; recombinase; stressor; tool

DESCRIPTION (provided by applicant): Opioids are effective analgesics but also carry a high abuse liability. Even after prolonged abstinence, former opioid addicts can remain vulnerable to relapse, particularly under stressful conditions. Most of the focus on opioid addiction and relapse mechanisms have centered on traditional dopaminergic reward pathways. Fewer studies have examined the role of the serotonin (5-hydroxytryptamine; 5-HT) system in opioid addiction and relapse. Preliminary data in rodents indicate that stress interacts with opioid history to sensitize 5-HT dorsal raphe nucleus (DRN) neurons to GABAergic inhibition. More recent work identified a causal relationship between GABA signaling in the DRN and stress-induced opioid reinstatement. We hypothesize that this GABAergic sensitization results in serotonergic hypofunction and consequent dysphoric mood states which drive drug-seeking behaviors and therefore confer vulnerability to stress- induced opioid relapse. In the current application, we will employ two state-of-the-art genetic mutational strategies using the Cre-loxP system to engineer mice that are deficient in GABAA receptors selectively in the DRN or specifically in 5-HT neurons. First, we will confirm DRN- or 5-HT-specific deletion of the GABAA receptor in these mice using immunohistochemistry, electrophysiology and quantitative autoradiography. Next, we will test these mice in two complementary animal models of relapse in which a swim stress is used to reinstate previously extinguished morphine conditioned place-preference or self-administration. We predict that these mice will be protected from the GABAergic sensitization observed in the 5-HT DRN system following a stress-induced relapse model and will thus be less vulnerable to relapse in these two models. These studies will generate innovative animal models of opiate relapse resistance that will be a valuable tool to elucidate novel circuitry within the 5-HT DRN system that contribute to opiate relapse. This approach may identify novel targets for the treatment of opiate addiction and the prevention of relapse.

描述（由申请人提供）：阿片类药物是有效的镇痛药，但也具有很高的滥用可能性。即使在长期戒断后，前阿片类药物成瘾者仍然容易复发，特别是在压力条件下。对阿片类药物成瘾和复发机制的大部分关注都集中在传统的多巴胺能奖励途径上。很少有研究探讨血清素（5-羟色胺；5-HT）系统在阿片类药物成瘾和复发中的作用。啮齿动物的初步数据表明，压力与阿片类药物历史相互作用，使 5-HT 中缝背核 (DRN) 神经元对 GABA 能抑制敏感。最近的工作确定了 DRN 中的 GABA 信号传导与应激诱导的阿片类药物恢复之间的因果关系。我们假设这种 GABA 能致敏作用会导致血清素能功能减退和随之而来的烦躁情绪状态，从而驱动寻求药物的行为，从而导致压力诱发的阿片类药物复发的脆弱性。在当前的应用中，我们将采用两种最先进的基因突变策略，使用 Cre-loxP 系统来工程改造 DRN 或特别是 5-HT 神经元中选择性缺乏 GABAA 受体的小鼠。首先，我们将使用免疫组织化学、电生理学和定量放射自显影术确认这些小鼠中 GABAA 受体的 DRN 或 5-HT 特异性缺失。接下来，我们将在两种互补的复发动物模型中测试这些小鼠，其中使用游泳应激来恢复先前熄灭的吗啡条件性位置偏好或自我给药。我们预测，在应激诱导的复发模型之后，这些小鼠将免受 5-HT DRN 系统中观察到的 GABA 能致敏的影响，因此在这两种模型中将不易复发。这些研究将产生抗阿片类药物复吸的创新动物模型，这将成为阐明 5-HT DRN 系统内导致阿片类药物复吸的新型电路的宝贵工具。这种方法可能会确定治疗阿片成瘾和预防复发的新靶点。