PET Imaging of neurochemical transmission in cocaine use disorders

可卡因使用障碍(CUD)是一种慢性疾病，与多次复发和 禁欲。CUD的研究表明，大约60%到75%的戒毒者会在12个月内复发。 (Aharonovich等人，2003年；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开发 防止复发。基础研究假设大脑压力和抗压力/恢复能力之间存在不平衡 系统作为驱动成瘾中负面强化、渴求和复发的潜在机制 (Koob，2008)。伤害性阿片肽受体(NOP)是一种与伤害性阿片肽受体结合的神经肽(N/OFQ)。 大脑抗应激系统的关键组成部分。N/OFQ通过对抗 初级应激促进神经肽促肾上腺皮质激素释放因子(CRF)在大鼠脑内的功能作用 大脑(Ciccocioppo等人，2001年)。研究还表明，慢性肾功能衰竭和压力的急剧增加 在调节压力的大脑区域中，NOP受体的表达增加(~10%)，如 终纹的床核(Rodi等人，2008年)。用NOP放射性示踪剂[11C]NOP-1A进行PET研究 与健康对照组(HC)相比，CUD患者与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上调可能代表了大脑的一种适应机制 来抵消压力引起的皮质醇和促肾上腺皮质激素释放激素的增加。在这里，我们假设这种适应性是失败的 机制是导致慢性阻塞性肺疾病复发的原因。CUD受试者和HC将用[11C]NOP- 1静脉注射氢化可的松前后(目标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的区域的皮质醇和促肾上腺皮质激素释放激素。我们假设 氢化可的松诱导的[11C]NOP-1A结合(DVT)增加在CUD将比HC更小，并且 这将与在12周的随访中复发的时间减少有关。机械论研究也有 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 神经元和限制对可卡因的奖励(Murphy and Maidment，1999；Parker等人，2019年)。成象 在参与目标1的部分CUD受试者中，苯丙胺诱导的多巴胺释放将允许我们 中脑NOP受体表达与腹侧纹状体(VST)多巴胺释放的关系及其作用 增援(目标2)。这项研究中提出的目标有可能澄清N/OFQ和 CUD患者在压力、奖励和复发方面无明显差异。

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.