Pleasure, addiction, and hypocretin (orexin).
Pleasure, addiction, and hypocretin (orexin).
复制标题
DOI：
10.1016/b978-0-12-820107-7.00022-7
复制
发表时间：
2021
影响因子：
--
通讯作者：
Siegel JM
中科院分区：
文献类型：
--
作者：
McGregor R;Thannickal TC;Siegel JM
下丘脑分泌素（hypocretins/orexins）是1998年发现的。在2年内，这导致了人类嗜睡症的原因的发现，90%的下丘脑神经元含有这些肽的损失。进一步的研究表明，这些神经元不仅仅与清醒有关。相反，这些神经元在清醒时的愉快行为中是活跃的，而在厌恶刺激时则是沉默的。这在野生型小鼠、大鼠、猫和犬中观察到。在人类中也很明显，在愉快的活动中增加了Hcrt的释放，而在疼痛中减少了释放，达到了睡眠中的水平。我们发现，人类海洛因成瘾者，平均而言，增加了54%的可检测的Hcrt神经元的数量相比，“控制”人类的大脑，这些Hcrt神经元是大大小于控制大脑。我们发现，在小鼠中，慢性吗啡给药引起Hcrt神经元数量和大小的相同变化。我们在小鼠中的研究使我们能够确定Hcrt神经元数量变化的特异性、剂量反应关系、时间过程，并且阿片类药物后Hcrt神经元数量的增加不是由于神经发生。此外，我们发现小鼠大脑中的这些解剖学变化需要一个月或更长时间才能恢复到基线。人类发作性睡病，尽管他们的处方使用几种常见的成瘾性药物，没有显示出剂量递增或物质使用障碍的显着证据。类似地，已经消除肽的小鼠对成瘾具有抵抗力。这些发现与Hcrt神经元数量增加可能是阿片类药物或可卡因使用障碍的基础和维持的概念一致。
The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons containing these peptides. Further work demonstrated that these neurons were not simply linked to waking. Rather these neurons were active during pleasurable behaviors in waking and were silenced by aversive stimulation. This was seen in wild-type mice, rats, cats, and dogs. It was also evident in humans, with increased Hcrt release during pleasurable activities and decreased release, to the levels seen in sleep, during pain. We found that human heroin addicts have, on average, an increase of 54% in the number of detectable Hcrt neurons compared to “control” human brains and that these Hcrt neurons are substantially smaller than those in control brains. We found that in mice, chronic morphine administration induced the same changes in Hcrt neuron number and size. Our studies in the mouse allowed us to determine the specificity, dose response relations, time course of the change in the number of Hcrt neurons, and that the increased number of Hcrt neurons after opiates was not due to neurogenesis. Furthermore, we found that it took a month or longer for these anatomical changes in the mouse brain to return to baseline. Human narcoleptics, despite their prescribed use of several commonly addictive drugs, do not show significant evidence of dose escalation or substance use disorder. Similarly, mice in which the peptide has been eliminated are resistant to addiction. These findings are consistent with the concept that an increased number of Hcrt neurons may underlie and maintain opioid or cocaine use disorders.