Role of SK2 channels in morphine dependence

SK2通道在吗啡依赖中的作用

• 批准号: 10087911
• 负责人: Jose A Moron-Concepcion
• 金额: $ 37.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087911
• 关键词: AMPA Receptors; Abstinence; Affect; Apamin; Behavior; Behavioral; Behavioral Model; Biochemistry; Brain; Cell Nucleus; Code; Cues; Data; Dendritic Spines; Development; Dorsal; Drug Addiction; Electrophysiology (science); Glutamates; Health; Hippocampus (Brain); Image; Impairment; In Vitro; Laboratories; Lead; Learning; Link; Measures; Mediating; Memory; Modeling; Molecular; Morphine; Morphine Dependence; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Pathway interactions; Pharmaceutical Preparations; Play; Proteins; Relapse; Reporting; Rewards; Role; Self Administration; Series; Synapses; Testing; Training; Vertebral column; addiction; awake; behavioral pharmacology; calmodulin-dependent protein kinase II; conditioned place preference; conditioning; drug craving; drug relapse; drug reward; experience; experimental study; hippocampal pyramidal neuron; in vivo; microendoscopy; neural circuit; novel; novel therapeutics; opioid abuse; opioid use; optogenetics; preference; prevent; receptor; two-photon; virus genetics

Although significant advances in the treatment of opiate addiction have been made, relapse to opiate use after abstinence continues to impede successful treatment, highlighting the need for efforts to dissect the mechanism of opiate-dependent changes in brain function. Long-lasting associations between opiates and the context in which they are taken result in cues that lead to drug craving and ultimately relapse. The hippocampus has traditionally been recognized for its role in learning and memory but recent evidence has shown its critical role in the behavioral effects of opiates, probably via activation of hippocampal excitatory inputs to the reward pathway (i.e. Nucleus Accumbens, NAc). Several lines of evidence suggest that drug- induced contextual/cue memories are associated with molecular changes in hippocampal function and that these changes may be necessary for some behavioral effects of opiates. Results from our laboratory have revealed that AMPAR and NMDAR play a crucial role in opiate-induced contextual learning. In addition SK2 channels, which are functionally linked to NMDAR, are critically involved in coding contextual memories. Furthermore, we have recently found that context-dependent sensitization to morphine leads to the activation of SK2 channels in the hippocampus. SK2-mediated functional effects on activated spines may be responsible for the expression and reinstatement of morphine place preference behavior. We also have preliminary data showing that the intrahippocampal administration of the SK2 blocker, apamin, following conditioning training, blocks the expression of morphine CPP. However, there are no reports dissecting how SK2 channels influence learning for opiate-paired contextual/cue behavior. Our central hypothesis is that enhancement of SK2 function, via increased Ca2+ influx through NMDAR, in the hippocampus plays a critical role in the formation of the association between the drug reward experience and the context/cue. Our overall objective is to uncover the cellular mechanisms underlying morphine-induced activation of SK2 channels, and to investigate how the activation of hippocampal SK2 channels are integral for morphine-induced contextual/cue learned associations, using both the CPP and i.v. drug self-administration models. In Aim 1, we will determine the mechanisms by which SK2 channel function is increased following morphine contextual/cue associations. In Aim 2, we will define the requirement for enhanced SK2 channel function in the expression and reinstatement of morphine contextual/cue associations in vivo. In Aim 3, we will determine whether hippocampal excitatory inputs to the NAc are enhanced during morphine-contextual/cue associations and to measure the underlying SK2-mediated changes in hippocampal pyramidal neuronal networks. Studies proposed here offer potentially novel drug addiction treatments in targeting SK2 channels to prevent drug-context/cue associations and thus prevent relapse to opiate use.

虽然在阿片类药物成瘾的治疗方面已经取得了重大进展，但在阿片类药物成瘾后复吸的情况仍然存在。 禁欲继续阻碍成功的治疗，突出表明需要努力剖析 阿片依赖性改变脑功能的机制。阿片类药物与麻醉药品之间的长期联系 服用这些药物的环境会导致对药物的渴望并最终复发。的 海马体传统上被认为在学习和记忆中起作用，但最近的证据表明， 显示其在阿片类药物的行为效应中的关键作用，可能通过激活海马兴奋性神经元， 奖励通路的输入（即伏核，NAc）。一些证据表明药物- 诱导的背景/线索记忆与海马功能的分子变化有关， 这些变化可能是阿片类药物的某些行为效应所必需的。我们实验室的结果显示， 揭示了AMPAR和NMDAR在阿片诱导的情境学习中起着至关重要的作用。此外，SK2 在功能上与NMDAR相关的通道在编码上下文记忆中至关重要。 此外，我们最近发现，对吗啡的上下文依赖性敏化导致激活 海马体中SK2通道的数量SK2介导的对激活的棘的功能作用可能是负责 吗啡位置偏爱行为的表达和恢复。我们也有初步数据 显示在条件训练后，海马内施用SK 2阻断剂，apamin， 阻断吗啡CPP的表达。然而，没有研究SK2通道如何影响 学习阿片配对的上下文/线索行为。我们的中心假设是SK2的增强 通过NMDAR增加的Ca 2+内流，在海马中的功能在海马神经元的形成中起着关键作用。 药物奖励体验与背景/线索之间的关联。我们的总体目标是 吗啡诱导的SK2通道激活的细胞机制，并研究 海马SK2通道的激活是吗啡诱导的背景/线索学习的组成部分 关联，使用CPP和静脉内药物自我给药模型。在目标1中，我们将确定 SK2通道功能在吗啡上下文/线索关联后增加的机制。在 目标2，我们将在表达和恢复中定义增强SK2通道功能的要求 吗啡上下文/线索协会在体内。在目标3中，我们将确定海马兴奋性 对NAc的输入在吗啡背景/线索关联期间得到增强，并测量潜在的 海马锥体神经元网络中SK2介导的变化。这里提出的研究可能提供 靶向SK2通道以防止药物背景/线索关联的新型药物成瘾治疗， 防止阿片类药物复发。

项目成果

Pain, negative affective states and opioid-based analgesics: Safer pain therapies to dampen addiction.

疼痛、负面情感状态和阿片类镇痛药：更安全的疼痛疗法可抑制成瘾。

• DOI: 10.1016/bs.irn.2020.09.002
• 发表时间: 2021
• 期刊: International review of neurobiology
• 作者: Massaly,Nicolas;Markovic,Tamara;Creed,Meaghan;Al-Hasani,Ream;Cahill,CatherineM;Moron,JoseA
• 通讯作者: Moron,JoseA