Dopamine and Glutamate Receptor Interactions

这是一份延长优异奖DA015835的申请。该奖项关注一个基本问题： 精神运动兴奋剂如何调节兴奋性突触突触可塑性？为了解决这个问题，我们 进行了AMPA受体转运的首次研究，AMPA受体转运是调节突触的关键机制 强度，在原代培养物中，来自脑桥核（NAc）和其他与奖励相关的大脑区域。我们 表明D1受体促进AMPA受体突触结合，提供了一种机制来解释 D1受体依赖的LTP易化和正常大脑中的学习。这个异常的接合 在不受调节的DA释放过程中的机制可能解释了在重复暴露过程中的适应不良可塑性 可卡因。在下一个资助期内，我们将继续解决有关可塑性的基本问题， 与奖励相关的大脑区域。特别是，我们想了解我们最近的研究背后的机制， 观察到NAc中的细胞表面AMPA受体水平在2种成瘾动物模型中增加： 行为敏感化和可卡因渴望的潜伏期。目的1将确定亚基组成的 NAc和其他成瘾相关脑区的AMPA受体群体关键是要知道亚基 组成，因为这决定了可塑性的许多特征。目标2将侧重于TARP（跨膜 AMPA受体调节蛋白），最近发现的调节AMPA受体的蛋白质家族 贩运和功能。我们将研究TARP在NAc神经元中的定位和功能，TARP在NAc神经元中的作用。 AMPA受体运输中的磷酸化，以及TARP在AMPA受体适应中的作用， 发生在行为敏感化和潜伏期。目标3将集中在突触缩放，一个重要的形式， 内稳态可塑性，其中AMPA受体的表面和突触表达在响应中上调 长时间的兴奋性传递活动减退，并下调对长时间的高兴奋性传递活动的反应。 活动我们将描述AMPA受体亚单位和TARPs的表达和定位的变化 在NAc神经元的突触缩放过程中，以及TARP磷酸化。我们假设突触 在可卡因戒断过程中，皮层输入活动减退引发的缩放是AMPA的原因。 在致敏和孵育期间NAc中的受体上调。公共卫生相关性：理解 成瘾的可塑性机制将有助于开发旨在“忘却”引发渴望的线索的疗法。

This is a request for extension of Merit Award DA015835. This Award focused on a fundamental question: how do psychomotorstimulants modulate synaptic plasticity at excitatory synapses? To address this, we conducted the first studies of AMPA receptor trafficking, a critical mechanism for regulating synaptic strength, in primary cultures from the nucleus accumbens (NAc) and other reward-related brain regions. We showed that D1 receptors facilitate AMPA receptor synaptic incorporation, providing a mechanism to explain D1 receptor-dependent facilitation of LTP and learning in the normal brain. Abnormal engagement of this mechanism during unregulated DA release may account for maladaptive plasticity during repeated exposure to cocaine. In the next funding period, we will continue to address fundamental questions about plasticity in reward-related brain regions. In particular, we want to understand mechanisms underlying our recent observation that cell surface AMPA receptor levels in the NAc are increased in 2 animal models of addiction: behavioral sensitization and incubation of cocaine craving. Aim 1will determine the subunit composition of AMPA receptor populations in NAc and other addiction-related brain regions. It is critical to know subunit composition, as this determines many features of plasticity. Aim 2 will focus on TARPs (transmembrane AMPA receptor regulatory proteins), a recently discovered family of proteins that regulates AMPA receptor trafficking and function. We will examine TARP localization and function in NAc neurons, the role of TARP phosphorylation in AMPA receptor trafficking, and the role of TARPs in AMPA receptor adaptations that occur in behavioral sensitization and incubation. Aim 3 will focus on synaptic scaling, an important form of homeostatic plasticity in which surface and synaptic expression of AMPA receptors upregulates in response to prolonged hypoactivity of excitatory transmission and downregulates in response to prolonged hyper- activity. We will characterize changes in expression and localization of AMPA receptor subunits and TARPs during synaptic scaling in NAc neurons, as well as TARP phosphorylation. We hypothesize that synaptic scaling, triggered by hypoactivity of cortical inputs during cocaine withdrawal, is responsible for AMPA receptor upregulation in the NAc during sensitization and incubation. Public health relevance: Understanding plasticity mechanisms in addiction will help develop therapies aimed at "unlearning" cues that elicit craving.