Nature2014-06-17 4:10 PM

由可卡因诱导的脑变化导致毒瘾复发 Contrasting forms of cocaine-evoked plasticity control components of relapse


上瘾药物被认为会劫持向各种不同的脑区域发送信号以控制行为反应的一体化脑中心(如伏核)中的神经回路。由于这样的操纵,与药物相关的提示信息会成为寻找药物行为的强大诱因,在停止用药(吸毒)后增加复发的机会。 在这项研究中,Christian Lüscher 及同事在来自前额皮质或背侧海马体的投射中,识别出了与小鼠伏核中的不同多巴胺能类群发生相互作用的特定神经通道所发生的由可卡因激发的改变。对这两个通道内由药物诱导的可塑性的操纵会消除寻找药物的行为,而仅仅破坏其中一个通道的可塑性则会降低对药物反应的分辨能力或对提示信息的反应强度。这些发现揭示了伏核上信息集成的可塑性机制,显示了药物(如可卡因)何以能够改变这种可塑性以让毒瘾复发。


Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cue-associated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA (N-methyl-D-aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking, whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders.






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