Neurobiological mechanisms of prescription opioid withdrawal

处方阿片类药物戒断的神经生物学机制

• 批准号: 10192688
• 负责人: ELENA H CHARTOFF
• 金额: $ 36.16万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192688
• 关键词: Abstinence; Acute; Address; Affect; Affective; Agonist; Amygdaloid structure; Anhedonia; Anxiety; Behavior; Biological Assay; Brain; Cocaine; Collaborations; Cues; Data; Development; Doctor of Philosophy; Drug usage; Electrophysiology (science); Epidemic; Exhibits; Exposure to; Female; Gender; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Government; High Prevalence; Intake; Laboratories; Link; Measures; Mediating; Medical; Microdialysis; Morphine; Morphine Dependence; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Oxycodone; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Public Health; Publishing; Rattus; Regulation; Relapse; Research; Rewards; Riluzole; Rodent; Role; Saline; Self Administration; Self Stimulation; Severities; Sex Differences; Signal Transduction; Slice; Structure of paraventricular nucleus of thalamus; Substance Withdrawal Syndrome; Surface; Symptoms; Synapses; Synaptic Transmission; Syndrome; System; Testing; Viral Vector; Withdrawal; Woman; Work; base; behavioral pharmacology; depressive symptoms; designer receptors exclusively activated by designer drugs; drug craving; drug relapse; experience; extracellular; glutamatergic signaling; insight; male; men; metabotropic glutamate receptor 2; negative affect; neurobiological mechanism; neurochemistry; novel; novel therapeutics; opioid use; opioid withdrawal; optogenetics; prescription drug abuse; prescription opioid; prescription opioid abuse; prevent; response; reward circuitry; sex; targeted treatment; trafficking; transmission process

Project Summary This R01 proposal was written in response to PA-16-233 “Prescription Drug Abuse”. Prescription opioid abuse is a major public health concern for both men and women. Although opioid addiction has historically exhibited a substantially higher prevalence in men, the gender gap is closing, underscoring the need to conduct research in both sexes. The opioid withdrawal syndrome, characterized by an acute physical syndrome and a long- lasting affective syndrome that includes anhedonia, anxiety, and drug cravings, is a major factor in escalation of opioid use and relapse. Cumulative work from our laboratory and others suggests that opioid withdrawal increases glutamate-mediated activation of the nucleus accumbens shell (NASh), which contributes to the withdrawal syndrome. For example, we have shown that morphine dependence is associated with increased neuronal surface expression of the AMPA glutamate receptor (AMPAR) GluA1 subunit in the NASh, and withdrawal-induced depressive-like states require NASh GluA1 AMPAR activation. It has also been shown that activation of glutamatergic projections from the paraventricular nucleus of the thalamus (PVT) to the NASh is required for expression of morphine withdrawal signs. However, this prior research has been conducted primarily in male rodents that experience withdrawal after experimenter-administered opioids. The regulation and role of NASh glutamatergic signaling in withdrawal from self-administered opioids in males and females is not known. The objective of this proposal is to build on these findings and examine how projection-specific (PVT to NASh) AMPAR-mediated signaling contributes to negative affective states triggered by withdrawal from oxycodone self-administration (SA) in male and female rats. Our central hypothesis is that oxycodone SA triggers projection-specific increases in AMPAR-mediated signaling in the NASh necessary for expression of negative affective states and relapse. We will address this hypothesis in 4 aims in which male and female rats will be exposed to long-access (LgA) oxycodone SA for 2 weeks followed by 2 weeks of abstinence. In Aims 1 and 2 we will examine how withdrawal from LgA oxycodone affects extracellular glutamate levels and synaptic transmission in the NASh using microdialysis (Aim 1) and slice electrophysiology paired with optogenetic activation of PVT to NASh projections (Aim 2). In Aims 3 and 4 we will determine if glutamate release and activation of AMPARs in the NASh is necessary for oxycodone withdrawal-induced negative affective states, as measured with intracranial self-stimulation. We will use chemogenetic modulation of PVT to NASh projections to regulate glutamate release (Aim 3) and viral vector-mediated expression of GluA1ct, which has been shown to block activity-dependent trafficking of GluA1 subunits, to regulate AMPAR transmission in the NASh (Aim 4). Data from these studies will establish a mechanistic link between projection-specific glutamatergic signaling in the NASh and oxycodone withdrawal-induced negative affective states in both males and females, which may ultimately enable development of gender-optimized opioid addiction treatments.

项目摘要 该R01提案是为了回应PA-16-233“处方药滥用”。处方滥用 尽管阿片类药物成瘾历史上已经暴露了 性别差距在男性中大大更高的患病率正在截断，强调进行研究的需求 在两个性别中。阿片类药物戒断综合征，其特征是急性物理综合征和长期 持久的情感综合征，包括Anhedonia，焦虑和毒品，是升级的主要因素 用绿核酸使用和缓解。我们实验室和其他人的累积工作表明卵虫类药物戒断 增加谷氨酸介导的伏伏核壳（NASH）的激活，这有助于 戒断综合征。例如，我们表明吗啡依赖性与增加有关 NASH中AMPA谷氨酸受体（AMPAR）GLUA1亚基的神经元表达 戒断引起的抑郁状态需要NASH GLUA1 AMPAR激活。也已经表明 从丘脑（pvt）到nash的谷氨酸能项目的激活 表达吗啡戒断迹象所需的。但是，这项先前的研究已经进行 在实验者管理阿片类药物后经历戒断的雄性啮齿动物的主要。法规 NASH谷氨酸能信号传导在从男性和女性中自我管理的阿片类药物退出的作用是 不知道。该提案的目的是建立这些发现并检查投影特定的方式 （PVT至NASH）AMPAR介导的信号传导导致戒断触发的负面情感状态 来自雄性和雌性大鼠的羟考酮自我给药（SA）。我们的中心假设是羟考酮SA 触发器在表达表达所需的NASH中AMPAR介导的信号传导的投影特异性增加 负面的情感状态和救济。我们将在男性和女性大鼠的4个目标中解决这一假设 将暴露于长期访问（LGA）羟考酮SA 2周，然后进行2周的禁欲。在目标1中 2我们将研究如何从LGA羟考酮中提取细胞外谷氨酸水平和突触 使用微透析（AIM 1）和SLICE电生理与光遗传学配对在NASH中传播 将PVT激活到NASH项目（AIM 2）。在目标3和4中，我们将确定谷氨酸是否释放和 对于羟考酮戒断引起的负面影响的状态，NASH中AMPAR的激活是必需的， 用颅内自刺激测量。我们将使用PVT的化学发生调制到NASH 调节谷氨酸释放（AIM 3）和病毒载体介导的GLUA1CT表达的项目 被证明可以阻止GLUA1亚基的活动依赖性运输，以调节AMPAR的传播 纳什（目标4）。这些研究的数据将在投影特异性之间建立机械联系 两名男性的NASH和羟考酮戒断诱导的负面情感状态中的谷氨酸能信号传导 和女性，最终可能使性别优化的阿片类药物成瘾治疗发展。