Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons
Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons
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DOI：
10.1038/npp.2015.168
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发表时间：
2016-01-01
影响因子：
7.6
通讯作者：
Thomas, Mark J.
中科院分区：
文献类型：
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作者：
Jedynak, Jakub;Hearing, Matthew;Thomas, Mark J.
反复接触可卡因或安非他明等精神兴奋剂可以促进寻求和服用药物的行为。在啮齿动物成瘾模型中，延髓核（NAc）中兴奋性多巴胺能神经传递的持续变化似乎驱动了这种药物诱导的行为可塑性。为了研究苯丙胺能信号的变化是否在特定的精神兴奋剂药物之间共享或专有，我们检查了重复安非他明或可卡因给药后小鼠的突触传递。重复安非他明或可卡因处理后10-14天，NAc壳中AMPA型谷氨酸受体介导的突触传递增强。这种突触增强被再次暴露于安非他明或可卡因而减弱。相比之下，在NAc核心，只有重复可卡因暴露增强突触传递，随后去增强的额外的可卡因，但不是安非他明注射在戒毒。为了更好地理解药物诱导的去增强作用，我们使用称为“浴中挑战”的离体模型复制了这些体内发现，并表明药物诱导的突触强度降低迅速发生（30分钟内），需要代谢型谷氨酸受体5（mGluR 5）的激活和NAc壳中的蛋白质合成，但不需要NAc核心。总体而言，这些数据表明安非他明引起的神经元回路变化的特异性，介绍了一种新的方法来研究药物挑战诱导的可塑性，并定义NAc壳介质多刺神经元作为一个主要网站的持久性AMPA型谷氨酸受体可塑性的两个广泛使用的精神兴奋剂药物。
Repeated exposure to psychostimulant drugs such as cocaine or amphetamine can promote drug-seeking and -taking behavior. In rodent addiction models, persistent changes in excitatory glutamatergic neurotransmission in the nucleus accumbens (NAc) appear to drive this drug-induced behavioral plasticity. To study whether changes in glutamatergic signaling are shared between or exclusive to specific psychostimulant drugs, we examined synaptic transmission from mice following repeated amphetamine or cocaine administration. Synaptic transmission mediated by AMPA-type glutamate receptors was potentiated in the NAc shell 10-14 days following repeated amphetamine or cocaine treatment. This synaptic enhancement was depotentiated by re-exposure to amphetamine or cocaine. By contrast, in the NAc core only repeated cocaine exposure enhanced synaptic transmission, which was subsequently depotentiated by an additional cocaine but not amphetamine injection during drug abstinence. To better understand the drug-induced depotentiation, we replicated these in vivo findings using an ex vivo model termed 'challenge in the bath,' and showed that drug-induced decreases in synaptic strength occur rapidly (within 30 min) and require activation of metabotropic glutamate receptor 5 (mGluR5) and protein synthesis in the NAc shell, but not NAc core. Overall, these data demonstrate the specificity of neuronal circuit changes induced by amphetamine, introduce a novel method for studying drug challenge-induced plasticity, and define NAc shell medium spiny neurons as a primary site of persistent AMPA-type glutamate receptor plasticity by two widely used psychostimulant drugs.