Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals
Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals
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DOI：
10.1073/pnas.1819978116
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发表时间：
2019-04-30
影响因子：
11.1
通讯作者：
Yang, Yihong
中科院分区：
文献类型：
--
作者：
Hu, Yuzheng;Salmeron, Betty Jo;Yang, Yihong
物质使用障碍 (SUD) 对个人、家庭和社会造成严重的负面影响。临床研究表明，一些长期使用兴奋剂的人在面临不良后果时能够减少药物的使用，而其他人则继续强迫性地使用药物。人们对这种二分法背后的机制知之甚少，这阻碍了针对目前尚无美国食品和药物管理局批准的药物治疗的疾病的有效个体化治疗的开发。在本研究中，使用甲基苯丙胺自我给药（SA）大鼠模型，同时存在足部电击，被认为与人类强迫性吸毒相似，我们发现SA行为与眶额皮质-背内侧纹状体“走”回路增加和前边缘皮质-腹外侧纹状体“停止”回路减少之间的平衡变化相关。重要的是，这种相关性仅在大鼠中出现，这些大鼠尽管接受了强度不断增加的足部电击，但仍然以相对较高的速度进行自我给药。虽然所有大鼠重复 SA 后停止电路功能连接变为负值，但“抗电击”大鼠在受到电击后表现出这种负连接性增强。相比之下，“对电击敏感”的老鼠在受到电击后表现出恢复到基线水平的能力。这些结果可能有助于指导新型无创脑刺激疗法，旨在恢复 SUD 中停止和运行回路之间的生理平衡。
Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal "go" circuit and a decreased prelimbic cortex-ventrolateral striatal "stop" circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, "shock-resistant" rats showed strengthening of this negative connectivity after shock exposure. In contrast, "shock-sensitive" rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs.