Role of hypocretin in opiate addiction and withdrawal

下丘脑分泌素在阿片成瘾和戒断中的作用

• 批准号: 10268966
• 负责人: JEROME M SIEGEL
• 金额: $ 64.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268966
• 关键词: Acute; Agonist; Amphetamines; Amygdaloid structure; Animals; Area; Attenuated; Axon; Back; Behavior; Brain; Buprenorphine; Cell Count; Cell Size; Cells; Chronic; Clozapine; Data; Dendrites; Distal; Dose; Drug Addiction; Drug resistance; Dynorphins; Electric Capacitance; Excision; Glutamates; Habenula; Half-Life; Heroin; Human; In Vitro; Injections; Intrinsic drive; Knockout Mice; Lead; Location; Mediating; Membrane; Methadone; Morphine; Morphine Dependence; Morphology; Motor; Motor Cortex; Mus; Naloxone; Narcolepsy; Nature; Neurons; Opiate Addiction; Opioid; Opioid Receptor; Opioid agonist; Oxides; Pattern; Peptides; Pharmaceutical Preparations; Physiological; Physiology; Population; Production; Property; Relapse; Reporting; Resistance; Ritalin; Role; Saline; Site; Sleep; Slice; Substance Withdrawal Syndrome; Substantia nigra structure; Symptoms; Synapses; Techniques; Testing; Thalamic structure; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Viral Vector; Wild Type Mouse; Withdrawal; Withdrawal Symptom; Work; addiction; density; designer receptors exclusively activated by designer drugs; dosage; gamma hydroxybutyrate; gamma-Aminobutyric Acid; hypocretin; interest; locus ceruleus structure; melanin-concentrating hormone; molecular marker; morphine administration; neurogenesis; noradrenergic; opiate tolerance; opioid epidemic; opioid use; opioid withdrawal; optogenetics; patch clamp; prevent; psychologic; receptor; response; sensory cortex

Project Summary/Abstract 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 阿片类药物危机的主要原因是阿片类药物的成瘾性和负面的生理学和 导致复发的戒断的心理影响。这些效果持续到最后几个月或几年 服用剂量。在最近的工作中，我们发现了神经元形态的最大变化 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％ 低载素（HCRT，Orexin）的水平和下胚素神经元的平均收缩率平均收缩。 相邻的黑色素浓缩激素神经元的数量或大小不会改变。我们看到了类似的长期 检测到的低载染细胞的数量和这些神经元的收缩率持续增加 长期但短期内野生型小鼠的脑降压素水平升高，吗啡 行政。降压素细胞数的增加不是由于神经发生，而是由于增加 在基线下未产生这些肽的可检测水平的神经元中产生低载素 状况。我们的试点数据，使用新开发的转基因小鼠，其中低载素神经元可以是 有选择地删除（DTA-HCRT小鼠），表明去除降压素神经元大大减少了戒断 与成瘾相关的区域中的症状和分子标记物的表达。 这些初步发现表明，封闭了降压素受体，降低的活性 低载素神经元，或将升高降低素神经元的升高降低到基线水平将有助于 在戒断和防止人鸦片瘾君子中复发。我们建议识别阿片受体 负责低载素细胞数和大小的变化。我们将从降压素神经元中记录 使用我们的慢性单位记录技术自由移动动物，以首次确定 这些细胞对系统性吗啡的反应随成瘾和戒断而变化。我们将确定如何 阿片给药诱导的新近识别的低载素产生细胞与基线不同 分布，投影和共同发射器的人口。我们将确定受体的变化和 阿片类药物使用体外技术产生的低螺旋蛋白神经元的膜生理。在我们的先前 我们发现，人类发作性睡病是由低载素细胞损失90％引起的。极大的兴趣 是人类麻醉剂很少滥用或升级治疗药物的剂量 苯丙胺，哌醋甲酯和伽马羟基丁酸每天需要逆转症状 经常在非麻醉剂中虐待。我们 在吗啡施用后发现小鼠，人类低胞菌素细胞的数量大大增加 吸毒者，以及对麻醉剂的降量降压素细胞数量的减少，他们对 吸毒成瘾表明，降骨素神经元在维持阿片类成瘾和 复发。操纵低载染素神经元可能是促进成瘾者戒断的关键。