PHOSPHORYLATION IN NEUROADAPTATIONS TO AMPHETAMINES

描述(改编自申请人的摘要)： 安非他明(AMPH)等精神活性药物的反复治疗 在药物经历中诱导的神经适应，可能有相似之处 其他突触可塑性和学习的模型。此应用程序将 专注于一种后期发展但长期持续的神经适应 由反复安非他明引起的：增强安非他明诱导的多巴胺(DA)释放。 在反复给药后，出现了三个新现象：1) 安非他明的急性DA释放增加；2)安非他明刺激DA释放 成为钙离子依赖的；以及3)调节 Amph&8209；介导的DA释放发生在蛋白激酶C到蛋白激酶A之间。 (PKA)和钙和钙调蛋白(CaM)依赖的蛋白激酶11(CaM) 九龙仓)。本应用程序的主要目标是了解 增强型Amph介导的蛋白质磷酸化/去磷酸化 DA在反复安眠药后释放。这个应用程序将实现三个目标。 1.确定PKA和CaM KLL激活是否在 平行或线性通路促进AMPH&8209；介导的大鼠DA释放 纹状体。2.研究PKA和CaM对DAT直接磷酸化的影响 KLL在增强的Amph中介导了重复Amph后DA的释放。3. 以确定重复之后的信令组件的调节。 间歇性的安眠药。4.确定DA的复活是否在 反复发作后，伏隔核与纹状体相似。 这项工作将开始确定神经生物学的生化基础 反复学习后的适应，可能表现出与学习的相似之处 模特们。因为多胺释放增强是通过反复治疗许多 毒品滥用，并可能参与到吸毒动机的激励中来， 了解增强型DA的生化基础是很重要的 放手。

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.