Jabourian Maritza, Pérez Sylvie, Ezan Pascal, Glowinski Jacques, Deniau Jean-Michel, Kemel Marie-Louise
INSERM U667, Collège de France, 11 place Marcelin Berthelot, F-75231 Paris Cedex 05, France.
Eur J Neurosci. 2007 Mar;25(5):1546-56. doi: 10.1111/j.1460-9568.2007.05375.x.
Information processing within the striatum is regulated by local circuits involving dopamine, cholinergic interneurons and neuropeptides released by recurrent collaterals of striatal output neurons. In the limbic-prefrontal territory of the dorsal striatum, enkephalin inhibits the NMDA-evoked release of acetylcholine directly through micro-opioid receptors (MORs) located on cholinergic interneurons and indirectly through MORs of output neurons of striosomes. In this territory, we investigated the consequence of changes in dopamine transmission, bilateral 6-hydroxydopamine-induced degeneration of striatal dopaminergic innervation or cocaine (acute and chronic) exposure on (i) MOR expression in both cholinergic interneurons and output neurons of striosomes, and (ii) the direct and indirect enkephalin-MOR regulations of the NMDA-evoked release of acetylcholine. Expression of MORs in cholinergic interneurons was preserved after 6-hydroxydopamine and down-regulated after cocaine treatments. Accordingly, the direct enkephalin-MOR control of acetylcholine release was preserved after 6-hydroxydopamine treatment and lost after cocaine exposure. Expression of MORs in output neurons of striosomes was down-regulated in the 6-hydroxydopamine situation and either preserved or up-regulated after acute or chronic cocaine exposure, respectively. Accordingly, the indirect enkephalin-MOR control of acetylcholine release disappeared in the 6-hydroxydopamine situation but surprisingly, despite preservation of MORs in striosomes, disappeared after cocaine treatment. Showing that MORs of striosomes are still functional in this situation, the MOR agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin inhibited the NMDA-evoked release of acetylcholine after cocaine exposure. Therefore, alteration in the regulation of cholinergic transmission by the enkephalin-MOR system might play a major role in the motivational and cognitive disorders associated with dopamine dysfunctions in fronto-cortico-basal ganglia circuits.
纹状体内的信息处理受局部回路调节，这些回路涉及多巴胺、胆碱能中间神经元以及纹状体输出神经元的回返侧支释放的神经肽。在背侧纹状体的边缘 - 前额叶区域，脑啡肽通过位于胆碱能中间神经元上的微阿片受体（MORs）直接抑制NMDA诱发的乙酰胆碱释放，并通过纹状体小体输出神经元的MORs间接抑制。在此区域，我们研究了多巴胺传递变化、双侧6 - 羟基多巴胺诱导的纹状体多巴胺能神经支配退化或可卡因（急性和慢性）暴露对（i）胆碱能中间神经元和纹状体小体输出神经元中MOR表达的影响，以及（ii）脑啡肽 - MOR对NMDA诱发的乙酰胆碱释放的直接和间接调节。6 - 羟基多巴胺处理后，胆碱能中间神经元中MOR的表达得以保留，而可卡因处理后则下调。相应地，6 - 羟基多巴胺处理后，脑啡肽 - MOR对乙酰胆碱释放的直接控制得以保留，而可卡因暴露后则丧失。在6 - 羟基多巴胺处理情况下，纹状体小体输出神经元中MOR的表达下调，而急性或慢性可卡因暴露后分别得以保留或上调。相应地，脑啡肽 - MOR对乙酰胆碱释放的间接控制在6 - 羟基多巴胺处理情况下消失，但令人惊讶的是，尽管纹状体小体中MOR得以保留，可卡因处理后却消失了。MOR激动剂[D - Ala(2),N - Me - Phe(4),Gly(5) - ol] - 脑啡肽在可卡因暴露后抑制了NMDA诱发的乙酰胆碱释放，表明纹状体小体中的MOR在这种情况下仍然具有功能。因此，脑啡肽 - MOR系统对胆碱能传递调节的改变可能在与额 - 皮质 - 基底神经节回路中多巴胺功能障碍相关的动机和认知障碍中起主要作用。
