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项目摘要/摘要：下丘脑泌素在阿片类药物成瘾和戒断中的作用 鸦片危机的主要原因是鸦片的成瘾性和负面的生理和 戒断的心理影响导致复发。这些影响持续数月或数年后，最后一次 剂量已采取。在最近的工作中，我们发现了可能是神经元形态学中最大的变化， 人类海洛因成瘾者的大脑;产生可检测到的神经元数量平均增加54% 下丘脑泌素（Hcrt，食欲素）水平，下丘脑泌素神经元体积平均缩小32%。 邻近的黑色素聚集激素神经元的数量和大小没有变化。我们看到了一个类似的长期- 检测到的下丘脑泌素细胞数量的持续增加和这些神经元的萎缩，伴随着 野生型小鼠在长期而非短期使用吗啡后，脑下丘脑泌素水平升高 局下丘脑泌素细胞数量的增加不是由于神经发生，而是由于下丘脑泌素细胞数量的增加。 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泌素 条件我们的试验数据，使用一种新开发的转基因小鼠，其中下丘脑泌素神经元可以 选择性缺失（DTA-Hcrt小鼠），表明去除下丘脑泌素神经元大大减少了戒断反应 症状以及成瘾相关区域中分子标记Fos和DeltaFosB的表达。 这些初步发现表明，阻断下丘脑泌素受体，降低下丘脑泌素受体的活性， 下丘脑泌素神经元，或降低升高的下丘脑泌素神经元数量回到基线水平将有助于 在戒断和预防复吸中的作用。我们建议识别阿片受体 负责下丘脑泌素细胞数量和大小的变化。我们将记录下丘脑分泌素神经元的 自由移动的动物使用我们的慢性单位记录技术，以确定，第一次， 这些细胞对全身吗啡的反应随着成瘾和戒断而改变。我们将决定如何 新鉴定的由阿片剂给药诱导的下丘脑分泌素产生细胞与基线不同 人口分布，投影和共同发射机。我们将确定受体的变化， 阿片类药物产生的下丘脑分泌素神经元的膜生理学。在我们之前的 我们的工作发现，人类发作性睡病是由平均90%的下视丘分泌素细胞损失引起的。很有趣的是， 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 他们每天服用安非他明、哌醋甲酯和γ-羟基丁酸来缓解症状， 在非发作性睡眠症人群中经常被滥用。下丘脑分泌素神经元的活动增加， 在小鼠中发现，吗啡给药后，人类下丘脑分泌素细胞的数量大大增加， 成瘾者，发作性睡病患者的下丘脑分泌素细胞数量大大减少， 药物成瘾，表明下丘脑分泌素神经元在维持阿片成瘾中起主要作用， 复发操纵下丘脑泌素神经元可能是促进成瘾者戒断的关键。

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.