PET Imaging of neurochemical transmission in cocaine use disorders

可卡因使用障碍（CUD）是一种慢性疾病，与许多复发和周期相关。 禁欲CUD的研究表明，约60%至75%的戒断成瘾者在12个月内复发 （Aharonovich等人，2003; Simpson等人，1999年）。记录特定的神经化学异常， 导致CUD患者复发的药物有可能加速药物的开发， 防止复发。基本的研究假设大脑压力和抗压力/弹性之间的不平衡 系统作为驱动负强化、渴望和成瘾复发的潜在机制 (Koob，2008）。孤啡肽（N/OFQ）是一种与伤害性阿片肽受体（NOP）结合的阿片受体， 大脑抗压力系统的关键组成部分N/OFQ通过抵消 促肾上腺皮质激素释放因子（CRF）在脑缺血再灌注损伤中的作用 脑（Ciccocioppo等人，2001年）。研究还表明，CRF和压力的急剧增加是 在调节压力的大脑区域，如大脑皮层， 终纹床核（Rodi等，2008年）。使用NOP放射性示踪剂[11 C]NOP-1A的PET研究 显示与健康对照（HC）相比，CUD中与NOP的结合增加（Narendran等人，2019年）。宠物 研究还表明，NOP受体在急性静脉注射后上调（~ 15%）， 氢化可的松激发（1 mg/Kg）。NOP上调可能代表脑中的一种适应性机制 来抵消压力引起的皮质醇和CRF的增加。在这里，我们假设这种适应性的失败 机制作为一个原因，导致复发的CUD。CUD受试者和HC将使用[11 C]NOP-进行研究 1A静脉注射氢化可的松激发前后（目的1）。氢化可的松被用作一种挑战 因为它会增加大脑中调节压力区域的皮质醇和CRF。我们假设 氢化可的松诱导的[11 C]NOP-1A结合（DVT）增加在CUD中相对于HC较小， 这将与在12周随访中复发的时间更短相关。机械研究也 显示N/OFQ作用于腹侧被盖区/中脑NOP受体以抑制多巴胺的放电 神经元并限制对可卡因的奖励（Murphy和Maidment，1999;帕克等人，2019年）。成像 在参与目标1的CUD受试者亚组中，安非他明诱导的多巴胺释放将使我们 将中脑NOP受体表达与腹侧纹状体（VST）多巴胺释放联系起来， 加强（目标2）。本研究提出的目标有可能阐明N/OFQ的作用， NOP在CUD中的压力、奖励和复发。

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.