Dopamine and Glutamate Receptor Interactions

这是一份延长DA015835荣誉奖的请求。该奖项聚焦于一个根本问题： 精神运动兴奋剂如何调节兴奋性突触的突触可塑性？为了解决这个问题，我们 首次对AMPA受体运输进行了研究，这是调节突触的关键机制 在原代培养中，伏隔核(NAC)和其他与奖励相关的大脑区域的力量。我们 D1R促进了AMPA受体突触的整合，为解释 D1R依赖的LTP易化和正常脑内的学习。这个不正常的交战 DA释放不受调控的机制可能是重复暴露时不适应可塑性的原因 为了可卡因。在下一个资助期，我们将继续解决有关可塑性的基本问题 与奖赏相关的大脑区域。特别是，我们想要了解我们最近 观察到在两种成瘾动物模型中NAC细胞表面AMPA受体水平升高： 可卡因渴求的行为敏化和潜伏。目标1将确定亚基组成 NAC和其他成瘾相关脑区的AMPA受体种群。了解亚基是至关重要的。 成分，因为这决定了可塑性的许多特征。目标2将重点放在Tarps(跨膜 AMPA受体调节蛋白)，这是最近发现的调节AMPA受体的蛋白质家族 贩卖和行使职能。我们将研究TARP在NAC神经元中的定位和功能，TARP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 发生在行为敏化和孵化过程中。目标3将专注于突触伸缩，这是 AMPA受体表面和突触表达上调的动态平衡可塑性 对长时间兴奋性传递的低活动和对长时间的高水平反应的下调 活动。我们将表征AMPA受体亚基和Tarp的表达和定位的变化 在NAC神经元的突触伸缩以及TARP的磷酸化过程中。我们假设突触 在可卡因戒断过程中，由皮质输入的低活性触发的伸缩是AMPA的原因 在致敏和孵化过程中NAC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”引发渴望的暗示的治疗方法。

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.