BLRD Senior Research Career Scientist Renewal Application

BLRD 高级研究职业科学家续签申请

• 批准号: 10451502
• 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: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451502
• 关键词: Acute; Agonist; Amphetamines; Anatomy; Animals; Attenuated; Back; Behavior; Brain; Buprenorphine; Cell Count; Cell Size; Cells; Chronic; Clozapine; Cocaine Dependence; Data; Dose; Drug Addiction; Drug resistance; Excision; Goals; Heroin; Human; Hypothalamic structure; In Vitro; Injections; Knockout Mice; Lead; Link; Location; Mediating; Membrane; Methadone; Morphine; Morphine Dependence; Morphology; Mus; Naloxone; Narcolepsy; Nature; Neurons; Obesity; Opiate Addiction; Opioid; Opioid Receptor; Oxides; Peptides; Pharmaceutical Preparations; Physiological; Physiology; Pilot Projects; Population; Production; Property; Publications; Rattus; Relapse; Reporting; Research; Ritalin; Role; Saline; Scientist; Site; Slice; Substance Withdrawal Syndrome; Symptoms; Synapses; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Viral Vector; Wild Type Mouse; Withdrawal; Withdrawal Symptom; Work; addiction; antagonist; career; designer receptors exclusively activated by designer drugs; dosage; gamma hydroxybutyrate; hypocretin; indexing; interest; melanin-concentrating hormone; molecular marker; morphine administration; neurogenesis; opioid epidemic; opioid use; opioid withdrawal; optogenetics; patch clamp; prevent; problem drinker; psychologic; receptor; response

Project Summary/Abstract: Role of hypocretin in opiate addiction and withdrawal Major causes of the opiate crisis are the addictive nature of opiates and the negative physiological and psychological effects of withdrawal that lead to relapse. These effects persist for months or years after the last dose is taken. In recent work we have found what may be the largest change in neuronal morphology in the brain of human heroin addicts; an average 54% increase in the number of neurons producing detectable levels of hypocretin (Hcrt, orexin), and an average 32% shrinkage in the volume of hypocretin neurons. Adjacent melanin concentrating hormone neurons do not change in number or size. We saw a similar long- lasting increase in the number of detected hypocretin cells and a shrinkage of these neurons, accompanied by elevated levels of brain hypocretin, in wild-type mice after longterm, but not short term, morphine administration. The increase in hypocretin cell number is not due to neurogenesis, but rather to increased production of hypocretin in neurons that do not produce detectable levels of these peptides under baseline conditions. Our pilot data, using a newly developed transgenic mouse in which hypocretin neurons can be selectively deleted (DTA-Hcrt mice), shows that removal of hypocretin neurons greatly reduces withdrawal symptoms and the expression of the molecular markers Fos and DeltaFosB in addiction related regions. These preliminary findings suggest that a blockade of hypocretin receptors, a decrease in of the activity of hypocretin neurons, or a reduction of elevated hypocretin neuronal number back to baseline levels would aid in withdrawal and prevent relapse in human opiate addicts. We propose to identify the opiate receptors responsible for the changes in hypocretin cell number and size. We will record from hypocretin neurons in freely moving animals using our chronic unit recording technique to determine, for the first time, how the response of these cells to systemic morphine changes with addiction and withdrawal. We will determine how the newly identifiable hypocretin producing cells induced by opiate administration differ from the baseline population in distribution, projection, and co-transmitters. We will determine the changes in the receptor and membrane physiology of hypocretin neurons produced by opiates using in vitro techniques. In our prior work we found that human narcolepsy is caused by an average 90% loss of hypocretin cells. Of great interest, is that human narcoleptics rarely abuse or escalate dosage of therapeutic drugs, even though the amphetamines, methylphenidate and gamma hydroxy-butyrate that they take daily to reverse symptoms are frequently abused in the non-narcoleptic population. The increased activity of hypocretin neurons that we find in mice after morphine administration, the greatly increased number of hypocretin cells in human addicts, and the greatly decreased number of hypocretin cells in narcoleptics, who are resistant to drug addiction, suggests that hypocretin neurons have a major role in maintaining opiate addiction and relapse. Manipulation of hypocretin neurons may be the key to facilitating withdrawal in addicts.

项目摘要/摘要：下丘脑分泌素在阿片成瘾和戒断中的作用 阿片类药物危机的主要原因是阿片类药物的成瘾性以及对生理和心理的负面影响。 导致复发的戒断心理影响。这些影响在上次发生后持续数月或数年 服用剂量。在最近的工作中，我们发现神经元形态的最大变化可能是什么 人类海洛因成瘾者的大脑；产生可检测的神经元数量平均增加 54% 下丘脑分泌素（Hcrt，食欲素）水平，下丘脑分泌素神经元体积平均缩小 32%。 相邻的黑色素浓缩激素神经元的数量或大小没有变化。我们看到了类似的长篇 检测到的下丘脑分泌素细胞数量持续增加，这些神经元萎缩，并伴有 野生型小鼠长期而非短期吗啡后大脑下丘脑分泌素水平升高 行政。下丘脑分泌素细胞数量的增加不是由于神经发生，而是由于增加 在基线下不产生可检测水平的这些肽的神经元中产生下丘脑分泌素 状况。我们的试验数据，使用新开发的转基因小鼠，其中下丘脑分泌素神经元可以 选择性删除（DTA-Hcrt 小鼠），表明去除下丘脑分泌素神经元可大大减少戒断症状 症状以及成瘾相关区域分子标记 Fos 和 DeltaFosB 的表达。 这些初步发现表明，下丘脑分泌素受体的阻断、下丘脑分泌素活性的降低 下丘脑分泌素神经元，或将升高的下丘脑分泌素神经元数量减少至基线水平将有助于 戒毒并防止人类阿片成瘾者复吸。我们建议鉴定阿片受体 负责下丘脑分泌素细胞数量和大小的变化。我们将从下丘脑分泌素神经元中记录 使用我们的慢性单位记录技术自由移动的动物，首次确定 这些细胞对全身吗啡的反应随着成瘾和戒断而变化。我们将决定如何 新发现的阿片类药物诱导的下丘脑分泌素产生细胞与基线不同 人口分布、预测和共同传播者。我们将确定受体的变化并 使用体外技术对阿片类药物产生的下丘脑分泌素神经元的膜生理学进行研究。在我们之前的 我们的研究发现，人类发作性睡病是由平均 90% 的下丘脑分泌素细胞损失引起的。非常感兴趣， 人类发作性睡病患者很少滥用或增加治疗药物的剂量，尽管 他们每天服用以逆转症状的安非他明、哌醋甲酯和γ-羟基丁酸是 在非发作性睡病人群中经常被滥用。我们发现下丘脑分泌素神经元的活性增加 发现给小鼠注射吗啡后，人类的下丘脑分泌素细胞数量大大增加 成瘾者，以及发作性睡病患者的下丘脑分泌素细胞数量大大减少，这些人对药物有抵抗力 药物成瘾，表明下丘脑分泌素神经元在维持阿片成瘾和 复发。操纵下丘脑分泌素神经元可能是促进成瘾者戒断的关键。