Cocaine facilitates glutamatergic transmission and activates lateral habenular neurons.
Cocaine facilitates glutamatergic transmission and activates lateral habenular neurons.
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DOI：
10.1016/j.neuropharm.2013.01.008
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发表时间：
2013-07
影响因子：
4.7
通讯作者：
Ye JH
中科院分区：
文献类型：
--
作者：
Zuo W;Chen L;Wang L;Ye JH
行政管理可以是有益的，也可以是有害的。虽然人们已经花了很多精力来研究奖励效应，但可卡因引起的厌恶感的潜在机制仍然不清楚。越来越多的证据表明，外侧缰核（LHb），一个小的上丘脑结构，在包括可卡因在内的许多成瘾药物的厌恶反应中起着关键作用。然而，可卡因对LHb神经元的影响还没有得到很好的研究。在这里，我们表明，在大鼠急性脑切片，可卡因去极化LHb神经元，并加速其自发放电。AMPA和NMDA谷氨酸受体拮抗剂，6，7-二硝基喹喔啉-2，3-二酮，DL-2-氨基-5-膦酰基戊酸，减弱可卡因诱导的加速。此外，可卡因浓度依赖性地增强兴奋：增强幅度，但减少了成对的脉冲比的电刺激引起的EPSC，并增加自发EPSC的频率在存在和不存在的河豚毒素。多巴胺和多巴胺D1（SKF 38393）和D2（喹吡罗）受体的激动剂，以及多巴胺转运蛋白阻滞剂（GBR 12935），模拟可卡因的作用。相反，D1（SKF 83566）和D2（雷氯必利）拮抗剂大大减弱了可卡因对EPSC和放电的影响。总之，我们的研究结果提供了证据表明，可卡因可能主要通过增加LHb中的多巴胺水平来激活LHb神经元上产生突触的多巴胺能末梢上的D1和D2受体。这导致谷氨酸释放和LHb神经元活性的增加，并可能有助于体内观察到的可卡因的厌恶作用。
Cocaine administration can be both rewarding and aversive. While much effort has gone to investigating the rewarding effect, the mechanisms underlying cocaine-induced aversion remain murky. There is increasing evidence that the lateral habenula (LHb), a small epithalamic structure, plays a critical role in the aversive responses of many addictive drugs including cocaine. However, the effects of cocaine on LHb neurons are not well explored. Here we show that, in acute brain slices from rats, cocaine depolarized LHb neurons and accelerated their spontaneous firing. The AMPA and NMDA glutamate receptor antagonists, 6, 7-dinitroquinoxaline-2, 3-dione, DL-2-amino-5-phosphono-valeric acid, attenuated cocaine-induced acceleration. In addition, cocaine concentration-dependently enhanced glutamatergic excitation: enhanced the amplitude but reduced the paired pulse ratio of EPSCs elicited by electrical stimulations, and increased the frequency of spontaneous EPSCs in the absence and presence of tetrodotoxin. Dopamine and the agonists of dopamine D1 (SKF 38393) and D2 (quinpirole) receptors, as well as the dopamine transporter blocker (GBR12935), mimicked the effects of cocaine. Conversely, both D1 (SKF 83566) and D2 (raclopride) antagonists substantially attenuated cocaine’s effects on EPSCs and firing. Together, our results provide evidence that cocaine may act primarily via an increase in dopamine levels in the LHb that activates both D1 and D2 receptors on the glutamatergic terminals which make synapses on LHb neurons. This leads to an increase in glutamate release and LHb neuron activity, and may contribute to the aversive effect of cocaine observed in vivo.
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影响因子：
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作者：
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通讯作者：
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