Cocaine Modulation of Synapses onto Dopamine Neurons

摘要 辨别补药机制(S)是认识补药的关键一步 强化学习机制，但到目前为止被证明是难以捉摸的。腹侧的多巴胺神经元 位于中脑腹侧的被盖区和黑质致密部是中枢。 药物强化的轨迹。即使一次接触可卡因也足以改变突触传递到 多巴胺神经元，关注AMPA介导的突触后可塑性机制 受体(AMPAR)。大多数AMPAR对钙离子不通透(CI-AMPAR)，而缺乏 GluR2亚基对钙离子具有通透性(CP-AMPAR)。一种称为校正的生物物理特性是 通常用于区分CP-AMPAR和更常见的CI-AMPAR。这是人们普遍接受的 可卡因暴露改变多巴胺神经元上AMPAR突触电流的整流性，而不影响 释放概率的测量，指出突触可塑性的突触后机制。然而，我们的新产品 数据挑战了这样的假设，即纠正足以推断AMPAR亚单位组成，并且 释放概率足以评估突触前效应。相反，我们的数据显示， 易释放的囊泡池可以在不改变释放的情况下有力地改变突触前的效应 突触前机制可以影响AMPAR突触电流的整流特性。 根据我们的数据，我们假设突触前机制有助于突触的变化 可卡因暴露后的多巴胺神经元。我们将首先测试多巴胺神经元的AMPAR特性 在隔离突触后机制的条件下，来自幼稚和可卡因处理的小鼠。到时候我们会的 追踪检测突触前改变是否有助于可卡因诱导的突触可塑性。 突触前效应和AMPAR亚单位组成具有重要的功能后果，范围包括 调节突触后细胞精确跟踪高频突触活动的能力 可能引发可塑性或成瘾等病理改变的CA2内流。圆满完成拟议的研究 有可能揭示突触对多巴胺神经元突触可塑性的新机制 在接触滥用药物后。

Abstract Identification of the mechanism(s) responsible for drug reinforcement is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, are a central locus for drug reinforcement. Even a single exposure to cocaine is sufficient to alter synaptic transmission to dopamine neurons, with attention focused on postsynaptic mechanisms of plasticity mediated by AMPA receptors (AMPARs). Most AMPARs are impermeable to Ca2+ (CI-AMPAR) whereas receptors that lack the GluR2 subunit are permeable to Ca2+ (CP-AMPAR). A biophysical characteristic known as rectification is commonly used to differentiate CP-AMPARs from the more common CI-AMPARs . It is commonly accepted that cocaine exposure alters rectification of AMPAR synaptic currents on dopamine neurons without affecting measures of release probability, pointing to postsynaptic mechanisms of synaptic plasticity. However, our new data challenges the assumptions that rectification is sufficient to infer AMPAR subunit composition and that release probability is sufficient to assess presynaptic efficacy. Rather, our data shows that changes in the readily-releasable pool of vesicles can robustly alter presynaptic efficacy without a change in the release probability and that presynaptic mechanisms can affect rectification properties of AMPAR synaptic currents. Based on our data, we hypothesize that presynaptic mechanisms contribute to synaptic changes in dopamine neurons following cocaine exposure. We will first test AMPAR properties in dopamine neurons from naïve and cocaine-treated mice under conditions that isolate postsynaptic mechanisms. We will then follow up to test whether presynaptic changes contribute to synaptic plasticity induced by cocaine exposure. Presynaptic efficacy and AMPAR subunit composition have important functional consequences ranging from regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and mediating Ca2+ influx that can trigger plasticity or pathology like addiction. Successful completion of the proposed studies has potential to reveal novel mechanisms underlying synaptic plasticity at synapses onto dopamine neurons following exposure to drugs of abuse.