Kappa-Opioid Receptor Mediated Regulation of Dopamine Transport

Kappa-阿片受体介导的多巴胺转运调节

• 批准号: 7992951
• 负责人: SAMMANDA RAMAMOORTHY
• 金额: $ 34.39万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992951
• 关键词: Acute; Affect; Agonist; Anhedonia; Animals; Antidepressive Agents; Attenuated; Behavior; Behavioral; Binding; Brain; Brain region; Cell physiology; Cocaine; Consensus; Data; Development; Disease; Dopamine; Dynorphins; Extracellular Space; Human; Individual; Ligands; Link; Mediating; Membrane Proteins; Mental Depression; Molecular Target; Mood Disorders; Moods; Motivation; Nerve; Neurons; Opioid Receptor; Outcome; Pathogenesis; Peptides; Phase; Phosphorylation; Phosphotransferases; Physiological; Physiology; Prevention; Psychostimulant dependence; Receptor Activation; Regulation; Role; Site; Societies; Synapses; System; Testing; Threonine; Tissues; Up-Regulation; Ventral Striatum; Withdrawal; addiction; aversive conditioning; cost; depressive symptoms; dopamine system; dopamine transporter; dopaminergic neuron; drug of abuse; drug withdrawal; dysphoria; extracellular; in vivo; insight; kappa opioid receptors; kinase inhibitor; monoamine; novel; presynaptic; prevent; prodynorphin; psychostimulant; public health relevance; receptor coupling; receptor-mediated signaling; relating to nervous system; therapy development; transmission process; uptake

DESCRIPTION (provided by applicant): Depression and addiction affect millions of individuals each year exerting untold costs on society. The dopamine transporter (DAT), a membrane protein that clears dopamine (DA) released into the extracellular space is a target of clinically used antidepressants and several drugs of abuse. ?-opioid receptors (KOR) are enriched in brain circuits that subserve mood and motivation and regulate the basal activity of DA neurons located therein. Upregulation of KOR systems has been implicated in the pathogenesis of depression and the mood dysregulation that characterizes withdrawal from cocaine and other drugs of abuse. Despite on-going efforts to develop orally effective KOR ligands for the treatment of depression and addiction, the downstream effectors upon which these agents act to affect behavior and DA transmission are unknown. The dysphoric and aversive effects of KOR agonists have been attributed to decreased DA release in the ventral striatum (VST). Importantly, however, KOR in VST are apposed to the dopamine transporter. Our studies show that KOR activation increases DAT activity through ERK1/2 dependent phosphorylation of threonine (Thr)53 of DAT and selective inhibition of ERK1/2 in the VST attenuates the aversive effects of KOR agonists. These findings identify a novel mechanism by which KOR ligands regulate presynaptic DA transmission and suggest that transporter dysregulation may be one mechanism underlying KOR-mediated alterations in mood and affect. The studies in this proposal will test the hypotheses that: KOR activation modulates DA dynamics and VST-dependent behaviors via ERK1/2-dependent phosphorylation and regulation of DAT. Specific Aim 1 will identify the cellular mechanisms of KOR-linked DAT modulation by determining whether KOR-mediated changes in DAT function and expression in the VST are associated with Thr53 phosphorylation and whether manipulations that prevent KOR-agonist evoked ERK1/2 activation and DAT phosphorylation in the VST attenuate KOR-mediated changes in DAT function. Specific Aim 2 will establish the relevance of this mechanism to the regulation of presynaptic DA transmission by determining whether manipulations that prevent KOR-agonist evoked ERK1/2 activation and DAT phosphorylation alter basal DA dynamics. Specific Aim 3 will determine the physiological relevance of KOR-ERK1/2 linked DAT modulation to the behavioral effects of KOR agonists and antagonists by assessing whether prevention of KOR-ERK1/2 linked DAT modulation in the VST attenuates the aversive and pro-depressive like effects of KOR agonists as well as the antidepressant-like effects of KOR antagonists. The role of KOR-ERK1/2 linked DAT modulation in mediating the efficacy of KOR agonists in preventing the locomotor stimulant effects of cocaine will also be assessed. Findings from these studies will enhance our understanding of the neural substrates upon which KOR ligands act to regulate mood and DA transmission. Furthermore, they will provide new insights as to the role of DAT phosphorylation in regulating synaptic DA clearance and behavior. PUBLIC HEALTH RELEVANCE: Kappa-opioid receptors are enriched in brain circuits that subserve mood and motivation and regulate the basal activity of both dopaminergic and serotoninergic neurons located therein. The proposed studies will test the hypothesis that kappa-opioid receptors affect monoamine transmission by activating kinase cascades that regulate the function of dopamine transporters. Outcomes from the proposal will enable identification of the molecular targets by which ?-opioid receptors regulate dopamine transmission and aid in the development of effective pharmacological agents for the treatment of addiction and other disease states resulting from aberrant monoamine transmission.

描述（由申请人提供）：抑郁症和成瘾症每年影响数百万人，给社会带来难以估量的成本。多巴胺转运蛋白 (DAT) 是一种膜蛋白，可清除释放到细胞外空间的多巴胺 (DA)，是临床使用的抗抑郁药和多种滥用药物的靶标。 β-阿片受体 (KOR) 富含大脑回路，可促进情绪和动机并调节位于其中的 DA 神经元的基础活动。 KOR 系统的上调与抑郁症和情绪失调的发病机制有关，情绪失调是戒除可卡因和其他滥用药物的特征。尽管人们一直在努力开发口服有效的 KOR 配体来治疗抑郁症和成瘾，但这些药物影响行为和 DA 传递的下游效应器尚不清楚。 KOR 激动剂的烦躁和厌恶作用归因于腹侧纹状体 (VST) 中 DA 释放的减少。然而，重要的是，VST 中的 KOR 与多巴胺转运蛋白相对应。我们的研究表明，KOR 激活通过 ERK1/2 依赖性 DAT 苏氨酸 (Thr)53 磷酸化增加 DAT 活性，并且选择性抑制 VST 中的 ERK1/2 可减弱 KOR 激动剂的厌恶作用。这些发现确定了 KOR 配体调节突触前 DA 传递的新机制，并表明转运蛋白失调可能是 KOR 介导的情绪和情感改变的潜在机制。本提案中的研究将测试以下假设：KOR 激活通过 ERK1/2 依赖性磷酸化和 DAT 调节来调节 DA 动力学和 VST 依赖性行为。具体目标 1 将通过确定 KOR 介导的 DAT 功能和 VST 表达的变化是否与 Thr53 磷酸化相关以及阻止 KOR 激动剂的操作是否引起 ERK1/2 激活和 DAT 磷酸化来确定 KOR 相关 DAT 调节的细胞机制VST 减弱 KOR 介导的 DAT 功能变化。具体目标 2 将通过确定阻止 KOR 激动剂诱发 ERK1/2 激活和 DAT 磷酸化的操作是否改变基础 DA 动力学来确定该机制与突触前 DA 传递调节的相关性。具体目标 3 将通过评估 VST 中 KOR-ERK1/2 相关 DAT 调节的预防是否会减弱厌恶和促抑郁等行为，确定 KOR-ERK1/2 相关 DAT 调节与 KOR 激动剂和拮抗剂行为效应的生理相关性。 KOR 激动剂的作用以及 KOR 拮抗剂的抗抑郁样作用。还将评估 KOR-ERK1/2 连接的 DAT 调节在介导 KOR 激动剂预防可卡因运动刺激作用的功效中的作用。这些研究的结果将增强我们对 KOR 配体调节情绪和 DA 传递的神经底物的理解。此外，他们还将提供关于 DAT 磷酸化在调节突触 DA 清除和行为中的作用的新见解。 公共健康相关性：κ-阿片受体在大脑回路中丰富，可促进情绪和动机，并调节位于其中的多巴胺能和血清素能神经元的基础活动。拟议的研究将验证卡帕阿片受体通过激活调节多巴胺转运蛋白功能的激酶级联影响单胺传递的假设。该提案的结果将能够识别α-阿片受体调节多巴胺传递的分子靶标，并有助于开发有效的药物制剂来治疗成瘾和由异常单胺传递引起的其他疾病状态。