Effects of morphine on the morphology of the hypocretin and MCH systems

吗啡对下丘脑分泌素和 MCH 系统形态的影响

• 批准号: 8625181
• 负责人: JEROME M SIEGEL
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625181
• 关键词: Accounting; Acute; Affect; Animals; Area; Arousal; Back; Behavioral; Brain; Cell Count; Cell Size; Cells; Cellular Morphology; Cerebrospinal Fluid; Cessation of life; Characteristics; Chronic; Data; Disease; Dopamine; Dopaminergic Cell; Dose; Drug Addiction; Drug resistance; Dynorphins; Eating; Functional disorder; Goals; HIV; Hepatitis; Heroin; Human; Hypothalamic structure; Immunohistochemistry; Individual; Infection; Investigation; Lead; Link; Location; Measures; Mediating; Mental Depression; Modification; Morphine; Morphine Dependence; Morphology; Mus; Naltrexone; Narcolepsy; Narcotic Antagonists; Nature; Neurofilament Proteins; Neurons; Opiates; Pathology; Peptides; Performance; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; Positive Reinforcements; Preclinical Drug Evaluation; Process; Progress Reports; Property; Recording of previous events; Regimen; Relapse; Reporting; Resistance; Rewards; Secure; Shock; Sleep; Sleep Wake Cycle; Source; Staining method; Stains; System; Techniques; Therapeutic; Time; Tissues; United States; Ventral Tegmental Area; Western Blotting; Withdrawal; Work; addiction; base; cocaine use; craving; dopaminergic neuron; experience; human data; hypocretin; improved; insight; intravenous injection; melanin-concentrating hormone; overdose death; positive emotional state; prescription opiate

DESCRIPTION (provided by applicant): Hypocretin (Hcrt, also called orexin) neurons have been implicated in the pathology underlying narcolepsy. We found that human narcoleptics, on average, have a 90% loss of Hcrt cells. Although the focus of most work has been on Hcrt's arousal function and its purported relation to food intake, our recent work has shown that activity of these cells is not simply related to arousal, food intake or "unearned" reward. Rather it is specifically linked to positive emotion and arousal during "work" for rewards (Progress Report). Hcrt neurons have major projections to dopamine neurons and appear to share and perhaps mediate aspects of dopamine's involvement in reward. Anecdotal data has long suggested that Hcrt deficient human narcoleptics are resistant to drug addiction. This finding has now been replicated in animal studies. Hcrt and MCH (melanin concentrating hormone) neurons are intermixed and appear to have reciprocal discharge profiles across the sleep-wake cycle. The number of Hcrt cells that we see in normal humans ranges from 51,000-83,000 based on the 15 normal brains we have counted. However, we recently received a "normal" brain that contained 114,000 Hcrt cells, 37% greater than the highest number of Hcrt cells (83,000) and 50% greater than the mean number (76,000), seen in controls. We also found that the size of Hcrt neurons in this individual was significantly smaller than that of controls. Further investigation revealed that this individual wa a former heroin addict, who had not taken addictive drugs for >10 years before his death. This suggested that opiate administration might alter the Hcrt system and that this alteration might be related to the craving experienced by former addicts. In pilot studies for this proposal, we then found that Hcrt cells in mice sacrificed after a 3 day period of continuous morphine administration were of normal number, but had reduced neuronal volume and altered morphology. This was not a subtle effect. Shrinkage averaged 23% in area after only 3 days of morphine administration. Furthermore, when we administered morphine for 7 and 14 days, we saw a substantial increase in Hcrt cell number. Such changes have never been reported in Hcrt neurons. In the same study, we found that morphine administration greatly decreased the number of identifiable MCH cells, a cell group not previously implicated in addiction. In contrast to Hcrt cells, the size and morphology of MCH cells was normal. The goal of the current proposal is to determine the nature and time course of morphological changes in Hcrt and MCH cells produced by short term morphine administration, by morphine addiction and by morphine withdrawal. We hypothesize that some of these changes are irreversible. We will study the behavioral correlates of these anatomical changes. These might include alterations in performance of positive vs. negatively reinforced tasks and modifications of sleep. We will secure additional human addict brains to replicate our initial observation of Hcrt cell number increase. Establishing that the properties of Hcrt cells can be altered in this "proof of principal study" might not only lead to a better understanding of drug addiction, but also lead to techniques to permanently and therapeutically alter and perhaps augment Hcrt function in disorders with Hcrt dysfunction including narcolepsy and depression.

描述(由申请人提供)： 促性腺激素释放激素(Hcrt，又称增食欲素)神经元与发作性睡病的发病机制有关。我们发现，人类发作性睡病患者平均有90%的Hcrt细胞丢失。尽管大多数研究的重点是Hcrt的唤醒功能及其与食物摄入的所谓关系，但我们最近的研究表明，这些细胞的活动不仅仅与唤醒、食物摄入或“不劳而获”的奖励有关。相反，它特别与“工作”期间的积极情绪和唤醒有关，以换取回报(进度报告)。Hcrt神经元有向多巴胺神经元的主要投射，似乎共享并可能介导了多巴胺参与奖赏的各个方面。坊间数据长期以来一直表明，Hcrt缺陷的人类发作性睡病患者对药物成瘾有抵抗力。这一发现现在已经在动物研究中得到了重复。Hcrt和MCH(黑色素浓缩激素)神经元混合在一起，在睡眠-觉醒周期中似乎有相互的放电特征。根据我们统计的15个正常大脑，我们在正常人身上看到的Hcrt细胞的数量从51,000到83,000不等。然而，我们最近得到了一个“正常”的大脑，它包含114,000个HCRT细胞，比HCRT细胞的最高数量(83,000个)多37%，比对照组的平均数量(76,000个)多50%。我们还发现，这个个体的Hcrt神经元的大小明显小于对照组。进一步调查发现，该人曾吸食海洛因，在他死前10年内没有吸食成瘾药物。这表明，阿片类药物的使用可能会改变HCRT系统，这种改变可能与曾经的吸毒者经历的渴望有关。在对这一提议的初步研究中，我们随后发现，连续给药3天后，小鼠的Hcrt细胞数量正常，但神经元体积减少，形态发生变化。这并不是一个微妙的影响。仅在注射吗啡3天后，面积平均缩小23%。此外，当我们给予吗啡7天和14天时，我们看到Hcrt细胞数量显著增加。这种变化在Hcrt神经元中从未报道过。在同一项研究中，我们发现吗啡注射大大减少了可识别的MCH细胞的数量，这是一个以前没有涉及成瘾的细胞群。与Hcrt细胞相比，MCH细胞的大小和形态正常。本提案的目的是确定短期吗啡给药、吗啡成瘾和吗啡戒断引起的Hcrt和MCH细胞形态变化的性质和时间进程。我们假设，其中一些变化是不可逆转的。我们将研究这些解剖变化的行为相关性。这些可能包括积极强化的任务与消极强化的任务的表现的变化，以及睡眠的改变。我们将获得额外的人类成瘾者大脑，以复制我们最初观察到的Hcrt细胞数量增加。在这项“主要研究的证据”中确定Hcrt细胞的特性可以改变，这不仅可能导致对药物成瘾的更好的理解，还可能导致永久性和治疗性改变Hcrt功能的技术，甚至可能增强Hcrt功能障碍，包括发作性睡病和抑郁症。