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 鸦片类药物危机的主要原因是鸦片类药物的成瘾性质以及消极的生理和心理因素 戒断会导致复发的心理影响。这些影响将持续数月或数年。 已经服药了。在最近的工作中，我们发现了可能是神经细胞形态上最大的变化 人类海洛因成瘾者的大脑；产生可检测到的神经元的数量平均增加54% 下丘脑肌素(Hcrt，增食欲素)水平，以及下丘脑神经元体体积平均收缩32%。 邻近的黑色素浓缩激素神经元在数量和大小上都不会改变。我们看到了一个类似的长- 检测到的下丘脑细胞数量的持续增加和这些神经元的萎缩，伴随着 长期(但非短期)吗啡治疗后野生型小鼠脑内下丘脑泌素水平升高 行政管理。下丘脑角蛋白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到的这些肽水平的神经元中产生的下丘脑素 条件。我们的试点数据，使用了一种新开发的转基因小鼠，在这种小鼠中，下丘脑可以 选择性缺失(DTA-Hcrt小鼠)，表明移除下丘脑神经元会大大减少戒断 症状和分子标志物Fos和DeltaFosB在成瘾相关区域的表达。 这些初步研究结果表明，阻断下丘脑肌酸受体，可降低脑血管活性。 下丘脑神经元，或将升高的下丘脑神经元数量减少到基线水平将有助于 在人类阿片成瘾者中戒断和防止复发。我们建议鉴定阿片受体 负责下丘脑细胞数量和大小的变化。我们将从下丘脑神经元录下 使用我们的慢性单位记录技术，第一次确定动物如何自由移动 这些细胞对全身性吗啡的反应随着成瘾和戒断而改变。我们将决定如何 阿片类药物给药诱导的新发现的下丘脑分泌细胞与基线不同。 人口在分布、预测和共同传播中。我们将确定受体的变化和 用体外技术研究鸦片类药物产生的下丘脑神经元膜生理学。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%的下丘脑泌素细胞丢失引起的。非常感兴趣的是， 人类发作性睡病患者很少滥用或增加治疗药物的剂量，即使 他们每天服用的扭转症状的苯丙胺、哌醋甲酯和羟丁酸伽玛是 在非发作性睡病人群中经常被滥用。我们发现下丘脑神经元活性的增加 在小鼠体内发现，注射吗啡后，人类体内的下丘脑细胞数量显著增加。 以及发作性睡病患者的下丘脑泌素细胞数量大幅减少，这些细胞对 药物成瘾，表明下丘脑神经元在维持阿片成瘾和 旧病复发。对下丘脑神经元的操纵可能是促进成瘾者戒断的关键。