Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence
Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence
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DOI：
10.1038/npp.2014.135
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发表时间：
2014-11-01
影响因子：
7.6
通讯作者：
Bowers, M. Scott
中科院分区：
文献类型：
--
作者：
Bull, Cecilia;Freitas, Kelen C. C.;Bowers, M. Scott
我们对星形胶质细胞在调节神经元功能和行为中发挥的积极作用的理解正在迅速扩大，但对星形胶质细胞在常见滥用物质的药物寻求行为中可能发挥的作用知之甚少。考虑到神经核与药物滥用和动机密切相关，我们试图确定神经核星形胶质细胞是否会影响禁欲后自我管理乙醇的动机。我们发现，表达胶质细胞酸性蛋白的星形胶质细胞的堆积密度增加，在戒断乙醇自我管理的过程中，在延髓核的核心（NAcore）。在核壳中未观察到变化。这增加了NAcore星形胶质细胞密度与乙醇的动机呈正相关。星形胶质细胞可以通过缝隙连接半通道相互沟通并影响神经元的活动。因此，研究了阻断间隙连接半通道对乙醇动机的影响。在阻断神经元和星形胶质细胞通道的剂量下，将间隙连接半通道阻断剂微量注射到NAcore中后，3周禁欲后自我施用乙醇的动机增加。相比之下，没有观察到影响后，显微注射的剂量，不被认为是阻止星形胶质细胞通道或显微注射后的剂量到核壳。此外，戒断3周后蔗糖的动机不受NAcore间隙连接半通道阻滞剂的影响。接下来，在NAcore星形胶质细胞中选择性地表达由设计者药物专门激活的设计者受体（DREADD），以测试星形胶质细胞刺激的效果。DREADD激活增加了初级星形胶质细胞中的细胞溶质钙，促进了对奖励性脑刺激的反应，并减少了3周禁欲后对乙醇的动机。这是第一个用星形胶质细胞特异性DREADD调节药物寻求行为的工作。总之，我们的研究结果表明，NAcore星形胶质细胞可以塑造自我管理乙醇的动机，这表明选择性刺激星形胶质细胞的配体的发展可能是一个成功的策略，以减轻乙醇寻求行为。
Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.