PHOSPHORYLATION IN NEUROADAPTATIONS TO AMPHETAMINES

描述（改编自申请人摘要）： 反复使用精神活性药物，如安非他明（AMPH）， 在药物经验诱导的神经适应中， 其他突触可塑性和学习的模型。此应用程序将 专注于一种晚期发展但持久的神经适应 重复AMPH引起：增强AMPH诱导的多巴胺（DA）释放。 AMPH重复给药后，出现三种新现象：1） AMPH刺激DA释放的作用 成为Ca 2+依赖性;和3）激酶开关调节 AMPH介导的DA释放发生在蛋白激酶C到蛋白激酶A之间 (PKA)钙离子和钙调蛋白依赖性蛋白激酶11（CaM Kll）。本应用程序的主要目标是了解 蛋白磷酸化/去磷酸化在增强AMPH介导的 反复AMPH后DA释放。本申请将实现三个目标。 1.为了确定PKA和CaM K11激活是否在一个细胞中起作用， 平行或线性途径增强AMPH介导的大鼠DA释放 纹状体2.通过PKA和CaM评估直接DAT磷酸化的作用 Kll在反复AMPH后增强的AMPH介导的DA释放中。3. 为了确定调节信号成分以下重复。 间歇性AMPH 4.确定DA释放是否在 重复AMPH后，中脑核与纹状体的变化相似。 这项工作将开始确定神经生物学的生化基础 重复AMPH后的适应，这可能与学习相似， 模型由于DA释放的增强是由许多药物的重复治疗引起的， 药物滥用，并可能参与药物滥用的激励动机， 重要的是要了解增强DA的生物化学基础， release.

DESCRIPTION(Adapted from applicant's abstract): Repeated treatment with psychoactive drugs such as amphetamine (AMPH) resuits in drug experience‑induced neuroadaptations which may have similarities to other models of synaptic plasticity and learning. This application will focus on one late‑developing but long‑lasting neuroadaptation elicited by repeated AMPH: enhanced AMPH‑induced dopamine (DA) release. Following repeated administration of AMPH, three novel phenomena occur: 1) acute DA release by AMPH is increased; 2) AMPH‑stimulated DA release becomes Ca2+ ‑dependent; and 3) A kinase switch in regulation of AMPH‑mediated DA release occurs from protein kinase C to protein kinase A (PKA) and Ca2+ and calmodulin (CaM)‑dependent protein kinase 11 (CaM Kll). The primary objective of this application is to understand the role of protein phosphorylation/dephosphorylation in the enhanced AMPH‑mediated DA release following repeated AMPH. This application will address three aims. 1. To determine whether PKA and CaM Kll activation are functioning in a parallel or linear pathway to enhance AMPH‑mediated DA release in rat striatum. 2. To assess the role of direct DAT phosphorylation by PKA and CaM Kll in the enhanced AMPH‑mediated DA release following repeated AMPH. 3. To determine the regulation of signalling components following repeated. intermittent AMPH. 4. Determine whether the reoulation of DA release in the nucleus accumbens is similar to that in striatum following repeated AMPH. This work wili begin to define the biochemical basis of of neurobiological adaptations following repeated AMPH, which may exhibit similarities to learning models. Because enhanced DA release is elicited by repeated treatment with many drugs of abuse, and may be involved in the incentive motivation to abuse drugs, it is important to understand the biochemical underpinnings of enhanced DA release.