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Neurobiological mechanisms of prescription opioid withdrawal

处方阿片类药物戒断的神经生物学机制

基本信息

批准号：
10436399
负责人：
ELENA H CHARTOFF
金额：
$ 8.58万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/10436399
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

项目摘要

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.

项目摘要本R 01提案是针对PA-16-233“处方药滥用”编写的。处方阿片类药物滥用是男性和女性的一个主要公共卫生问题。尽管阿片类药物成瘾在历史上表现出尽管男性的发病率高得多，但性别差距正在缩小，这突出表明有必要进行研究，在两性中。阿片类药物戒断综合征，其特征是急性躯体综合征和长期- 包括快感缺乏、焦虑和对药物的渴望在内的持久情感综合征是导致病情升级的主要因素阿片类药物的使用和复发。我们实验室和其他实验室的累积工作表明，阿片类药物戒断增加谷氨酸介导的核壳（NASh）活化，这有助于戒断综合征例如，我们已经表明，吗啡依赖与增加 NASh中AMPA谷氨酸受体（AMPAR）GluA 1亚基的神经元表面表达，和戒断诱导的抑郁样状态需要NASh GluA 1 AMPAR激活。还已显示激活从丘脑室旁核（PVT）到NASh的突触能投射，需要表达吗啡戒断症状。然而，这项先前的研究已经进行了主要是在实验者施用阿片类药物后经历戒断的雄性啮齿动物中。调控在男性和女性中，NASh神经元能信号在自我给药阿片类药物戒断中的作用是不知道。本提案的目的是在这些调查结果的基础上， (PVT NASh）AMPAR介导的信号传导有助于由戒断引发的负面情感状态雄性和雌性大鼠中羟考酮自我给药（SA）。我们的中心假设是羟考酮SA 触发NASh中AMPAR介导的信号传导的投射特异性增加，消极情感状态和复发。我们将在4个目标中解决这一假设，其中雄性和雌性大鼠将暴露于长期给药（LgA）羟考酮SA 2周，随后禁欲2周。目标1 和2，我们将研究从LgA羟考酮中撤出如何影响细胞外谷氨酸水平和突触使用微透析（Aim 1）和切片电生理学与光遗传学配对，激活PVT至NASh投射（目的2）。在目标3和4中，我们将确定谷氨酸释放和 NASh中AMPAR的激活对于羟考酮戒断诱导的负性情感状态是必需的，用颅内自我刺激测量。我们将使用化学遗传学调节PVT至NASh 预测，以调节谷氨酸释放（目的3）和病毒载体介导的表达GluA 1ct，其中有已显示阻断GluA 1亚基的活性依赖性运输，以调节AMPAR在细胞中的传递。 NASh（目标4）。来自这些研究的数据将建立特定项目之间的机械联系， NASh和羟考酮戒断诱导的两种雄性动物的负性情感状态中的多巴胺能信号传导和女性，这可能最终使性别优化的阿片类药物成瘾治疗的发展。