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Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour

机译：可卡因诱发的突触增强作用的逆转重置药物诱导的适应性行为

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Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction1. Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing2 and early neuroadaptive effects3 by inhibiting the dopamine transporter, thus causing a strong increase in mesolimbic dopamine. Among the many signalling pathways subsequently engaged, phosphoryla-tion of the extracellular signal-regulated kinase (ERK) in the nucleus accumbens4 is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (Dl)-receptor-dependent synaptic potentiation5 as well as in several behavioural adaptations6^8. A causal link between drug-evoked plasticity at identified synapses and behavioural adaptations, however, is missing, and the benefits of restoring baseline transmission have yet to be demonstrated. Here we find that cocaine potentiates excitatory transmission in Dl-receptor-expressing medium-sized spiny neurons (DIR-MSNs) in mice via ERK signalling with a time course that parallels locomotor sensitization. Depotentiation of cortical nucleus accumbens inputs by optogenetic stimulation in vivo efficiently restored normal transmission and abolished cocaine-induced locomotor sensitization. These findings establish synaptic potentiation selectively in DIR-MSNs as a mechanism underlying a core component of addiction, probably by creating an imbalance between distinct populations of MSNs in the nucleus accumbens. Our data also provide proof of principle that reversal of cocaine-evoked synaptic plasticity can treat behavioural alterations caused by addictive drugs and may inspire novel therapeutic approaches involving deep brain stimulation or transcranial magnetic stimulation.
机译：在许多突触中观察到药物诱发的突触可塑性，可能是成瘾行为适应的基础。机械研究始于分子药物靶标的鉴定。例如，可卡因通过抑制多巴胺转运蛋白发挥其增强作用2和早期的神经适应作用3，从而引起中脑边缘多巴胺的强烈增加。在随后参与的许多信号传导途径中，伏伏核中细胞外信号调节激酶（ERK）的磷酸化特别令人关注，因为它与NMDA受体和1型多巴胺（D1）受体依赖性突触有关。增强5，以及进行多种行为适应6 ^ 8。然而，在已确定的突触中，药物诱发的可塑性与行为适应之间没有因果关系，而且恢复基线传播的益处尚未得到证实。在这里，我们发现可卡因通过ERK信号转导了与运动敏化相平行的时程，从而增强了小鼠在表达D1受体的中型棘突神经元（DIR-MSNs）中的兴奋性传递。皮层伏隔核输入的去势通过体内光遗传学刺激有效地恢复了正常的传播并废除了可卡因诱导的运动敏化。这些发现可能通过在伏伏核中不同MSN种群之间造成失衡，从而选择性地将DIR-MSNs中的突触增强建立为成瘾核心成分的基础机制。我们的数据还提供了原理证明，可卡因诱发的突触可塑性的逆转可以治疗由成瘾性药物引起的行为改变，并可能激发涉及深部脑刺激或经颅磁刺激的新型治疗方法。

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  • 来源
    《Nature》 |2012年第7379期|p.71-75|共5页
  • 作者

    Vincent Pascoli; Marc Turiault; Christian Liischer;

  • 作者单位

    Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland;

    Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland;

    Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland,Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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