PET Imaging of neurochemical transmission in cocaine use disorders

可卡因使用障碍中神经化学传递的 PET 成像

基本信息

批准号：
10459233
负责人：
RAJESH NARENDRAN
金额：
$ 62.61万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459233
关键词：
Abstinence Acute Agonist Amphetamines Amygdaloid structure Animals Anxiety Apomorphine Award Behavior Binding Brain Brain region Chronic Chronic Disease Clinical Cocaine Cocaine use disorder Corticotropin-Releasing Hormone Development Dopamine Factor X Failure Goals Hippocampus (Brain)Hydrocortisone Image Individual Intravenous Investigation Lead Link Measures Midbrain structure Negative Reinforcements Neuropeptides Nociception Nucleus Accumbens Opioid Peptide Oral Outcome Measure Peptide Receptor Pharmaceutical Preparations Positron-Emission Tomography Psychological reinforcement Relapse Rewards Rodent Role Scanning Signal Transduction Stress Structure of terminal stria nuclei of preoptic region Substantia nigra structure System Time Ventral Striatum Ventral Tegmental Area addiction cooking craving dopaminergic neuron follow-up imaging study in vivo interest neurochemistry nociceptin prevent radiotracer receptor receptor expression receptor upregulation response stress resilience therapeutic target transmission process

项目摘要

Cocaine use disorder (CUD) is a chronic disorder associated with numerous relapses and periods of abstinence. Studies in CUD suggest that ~ 60 to 75% of abstinent addicts relapse over twelve months (Aharonovich et al., 2003; Simpson et al., 1999). Documenting specific neurochemical abnormalities that lead to relapse in individuals with CUD has the potential to accelerate the development of medications to prevent relapse. Basic investigations postulate an imbalance between brain stress and anti-stress/resilience systems as the underlying mechanism that drives negative reinforcement, craving, and relapse in addiction (Koob, 2008). Nociceptin (N/OFQ), which binds to the nociceptive opioid peptide receptors (NOP) is a critical component of the brain’s anti-stress system. N/OFQ exerts its anti-stress effect by counteracting the functional effects of the primary stress-promoting neuropeptide corticotrophin releasing factor (CRF) in the brain (Ciccocioppo et al., 2001). Studies have also shown that acute increases in CRF and stress are countered by increased NOP receptor expression (~ 10% ) in brain regions that regulate stress such as the bed nucleus of the stria terminalis (Rodi et al., 2008). PET studies with the NOP radiotracer [11C]NOP-1A show increased binding to NOP in CUD compared to healthy controls (HC) (Narendran et al., 2019). PET studies also show NOP receptors to upregulate (~ 15%) in response to an acute intravenous hydrocortisone challenge (1 mg/Kg). NOP upregulation may represent an adaptive mechanism in the brain to counteract stress-induced increases in cortisol and CRF. Here, we postulate a failure in this adaptive mechanism as a reason that leads to relapse in CUD. CUD subjects and HC will be studied with [11C]NOP- 1A before and after an intravenous hydrocortisone challenge (aim 1). Hydrocortisone is used as a challenge because it increases cortisol and CRF in brain regions that regulate stress. We hypothesize that hydrocortisone-induced increases in [11C]NOP-1A binding (DVT) will be smaller in CUD relative to HC, and this will be associated with less time to relapse in a 12-week follow up. Mechanistic studies have also shown N/OFQ to act on ventral tegmental area/midbrain NOP receptors to inhibit the firing of dopamine neurons and limit reward to cocaine (Murphy and Maidment, 1999; Parker et al., 2019). Imaging amphetamine-induced dopamine release in a subset of CUD subjects who participate in aim 1 will allow us to link midbrain NOP receptor expression with ventral striatum (VST) dopamine release and examine its role in reinforcement (aim 2). The aims proposed in this study have the potential to clarify the role of N/OFQ and NOP in stress, reward, and relapse in CUD.

可卡因使用障碍 (CUD) 是一种慢性疾病，与多次复发和周期相关 CUD 研究表明，约 60% 至 75% 的戒瘾者在 12 个月内会复发。（Aharonovich 等，2003；Simpson 等，1999）记录了特定的神经化学异常。导致 CUD 个体复发的药物有可能加速药物的开发预防复发。基本研究假设大脑压力和抗压力/恢复力之间存在不平衡。系统作为驱动成瘾的负强化、渴望和复发的潜在机制 (Koob, 2008) 伤害感受肽 (N/OFQ) 与伤害性阿片肽受体 (NOP) 结合。 N/OFQ 是大脑抗应激系统的重要组成部分，通过抵消主要促应激神经肽促肾上腺皮质激素释放因子（CRF）的功能作用研究还表明，CRF 和压力的急剧增加会影响大脑（Ciccocioppo 等，2001）。调节压力的大脑区域中 NOP 受体表达增加 (~ 10%) 终纹床核（Rodi 等人，2008 年使用 NOP 放射性示踪剂 [11C]NOP-1A 进行 PET 研究）。与健康对照 (HC) 相比，CUD 中与 NOP 的结合增加（Narendran 等人，2019）。研究还表明，NOP 受体响应急性静脉注射而上调 (~ 15%) 氢化可的松挑战（1 mg/Kg）。 NOP 上调可能代表大脑中的一种适应性机制。为了抵消压力引起的皮质醇和 CRF 的增加，我们假设这种适应性失败了。机制作为导致 CUD 受试者和 HC 复发的原因，将用 [11C]NOP- 进行研究。 1A 使用氢化可的松静脉注射之前和之后（目标 1）。因为它会增加调节压力的大脑区域的皮质醇和 CRF。相对于 HC，氢化可的松诱导的 [11C]NOP-1A 结合 (DVT) 增加在 CUD 中较小，并且在 12 周的随访中，这也与更短的复发时间有关。显示 N/OFQ 作用于腹侧被盖区/中脑 NOP 受体，抑制多巴胺的放电神经元并限制对可卡因的奖励（Murphy 和 Maidment，1999；Parker 等人，2019）。在参与目标 1 的 CUD 受试者子集中，安非他明诱导的多巴胺释放将使我们能够将中脑 NOP 受体表达与腹侧纹状体 (VST) 多巴胺释放联系起来并检查其作用本研究提出的目标有可能阐明 N/OFQ 和的作用。 NOP 涉及 CUD 中的压力、奖励和复发。