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，但也承担高虐待责任。即使长期节制，前阿片类药物上瘾者也可能仍然容易发生复发，尤其是在压力条件下。大多数对阿片类药物成瘾和复发机制的关注都集中在传统的多巴胺能奖励途径上。较少的研究研究了5-羟色胺（5-羟基丙胺； 5-HT）系统在阿片类成瘾和复发中的作用。啮齿动物中的初步数据表明，应力与阿片类药物病史相互作用，以使5-HT背raphe核（DRN）神经元对GABA能抑制作用敏感。最近的工作确定了DRN中GABA信号传导与应力诱导的阿片类药物恢复原状之间的因果关系。我们假设这种GABA能敏化会导致血清素能功能障碍和随之而来的烦躁情绪状态，从而驱动寻求药物的行为，从而赋予压力引起的阿片类药物复发的脆弱性。在当前的应用中，我们将使用CRE-LoxP系统采用两种最先进的遗传突变策略，以在DRN或5-HT神经元中选择性地缺乏GABAA受体缺乏。首先，我们将使用免疫组织化学，电生理学和定量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模型中测试这些小鼠，其中使用游泳应力来恢复先前灭绝的吗啡条件的偏爱或自我给药。我们预测，这些小鼠将受到压力诱导的复发模型后在5-HT DRN系统中观察到的GABA能敏化的保护，因此在这两个模型中不太容易发生复发。这些研究将产生鸦片复发性抗性的创新动物模型，这将是阐明有助于阿片反复发的5-HT DRN系统中新型电路的宝贵工具。这种方法可以确定治疗阿片类成瘾和预防复发的新目标。