Bellone Camilla, Lüscher Christian
Department of Basic Neurosciences, University of Geneva, 1 Michel Servet, CH-1211 Geneva, Switzerland.
Nat Neurosci. 2006 May;9(5):636-41. doi: 10.1038/nn1682. Epub 2006 Apr 2.
Drugs of abuse induce long-lasting changes in neural circuits that may underlie core components of addiction. Here we focus on glutamatergic synapses onto dopamine (DA) neurons of the ventral tegmental area (VTA). Using an 'ex vivo' approach in mice, we show that a single injection of cocaine caused strong rectification and conferred sensitivity to the polyamine Joro spider toxin (JST) of AMPAR-mediated excitatory postsynaptic currents (AMPAR EPSCs), indicating the recruitment of receptors that lack GluR2. This qualitative change in transmission was paralleled by an increase in the AMPAR:NMDAR ratio and was prevented by interfering with the protein interacting with C kinase-1 (PICK1) in vivo. Activation of metabotropic glutamate receptors (mGluR1s) by intraperitoneal injection of a positive modulator depotentiated synapses and abolished rectification in slices of cocaine-treated mice, revealing a mechanism to reverse cocaine-induced synaptic plasticity in vivo.
滥用药物会在神经回路中引发持久变化，这些变化可能是成瘾核心成分的基础。在此，我们聚焦于腹侧被盖区（VTA）多巴胺（DA）神经元上的谷氨酸能突触。通过在小鼠中采用“离体”方法，我们发现单次注射可卡因会导致强烈的整流作用，并使AMPA受体介导的兴奋性突触后电流（AMPAR EPSCs）对多胺类Joro蜘蛛毒素（JST）敏感，这表明募集了缺乏GluR2的受体。这种传递上的质性变化与AMPAR:NMDAR比值的增加同时出现，并且在体内通过干扰与C激酶-1相互作用的蛋白（PICK1）得以预防。腹腔注射正性调节剂使代谢型谷氨酸受体（mGluR1s）激活，使可卡因处理小鼠脑片中的突触去增强并消除整流作用，揭示了一种在体内逆转可卡因诱导的突触可塑性的机制。
