Role of SK2 channels in morphine dependence

尽管在治疗阿片成瘾方面取得了重大进展，但在以下情况下再次使用阿片成瘾 禁欲继续阻碍成功的治疗，突显出需要努力剖析 阿片类药物依赖性脑功能改变的机制。鸦片类药物和 服用这些药物的背景会导致线索，导致对药物的渴望并最终复发。这个 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行为效应中的关键作用，可能是通过激活海马区的兴奋性 奖赏通路的输入(即伏隔核，NAC)。有几条证据表明，毒品- 诱导的上下文/线索记忆与海马体功能的分子变化有关，并且 这些变化对于鸦片类药物的某些行为影响可能是必要的。我们实验室的结果是 研究表明，AMPAR和NMDAR在阿片类药物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相连的通道，对语境记忆的编码起着至关重要的作用。 此外，我们最近发现，对吗啡的上下文依赖敏化导致激活 在海马区的SK2通道。SK2介导的激活脊椎功能效应可能是原因之一 用于表达和恢复吗啡位置偏爱行为。我们也有初步数据 表明在条件性训练后，海马区内注射SK2阻滞剂阿帕明， 阻断吗啡CPP的表达。然而，目前还没有关于SK2渠道如何影响的报道 学习鸦片配对的上下文/线索行为。我们的中心假设是SK2的增强 功能，通过增加钙离子内流通过NMDAR，在海马区发挥关键作用 药物奖励体验与上下文/线索之间的关联。我们的总体目标是发现 吗啡诱导SK2通道激活的细胞机制，并研究 海马SK2通道的激活对吗啡诱导的情境/线索习得是不可或缺的 联合，使用CPP和静脉注射。药物自主给药模式。在目标1中，我们将确定 在吗啡背景/线索关联之后，SK2通道功能增强的机制。在……里面 目标2，我们将在表达式和恢复中定义增强SK2通道功能的要求 体内吗啡背景/线索关联的研究。在目标3中，我们将确定海马区兴奋性 在吗啡-语境/线索联想期间，对NAC的输入得到增强，并测量潜在的 SK2介导的海马锥体神经元网络的变化。这里提出的研究可能提供 针对SK2通道的新型药物成瘾治疗方法，以防止药物上下文/线索关联，从而 防止复吸鸦片类药物。

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.