Garcinol: A Magic Bullet of Amnesia for Maladaptive Memories?
Garcinol: A Magic Bullet of Amnesia for Maladaptive Memories?
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Garcinol：适应不良记忆失忆症的灵丹妙药？
DOI：
10.1038/npp.2016.165
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
McLaughlin,RyanJ
中科院分区：
文献类型：
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作者：
Fuchs,RitaA;McLaughlin,RyanJ
根据美国最新的统计数据，约15%的12岁及以上的人报告一生中至少使用过一次可卡因（全国药物使用和健康调查，2015年），可卡因仍然是与药物相关的急诊室就诊期间最常被引用的滥用药物（药物滥用警告网络，2014年）。复发，经常因暴露于与药物相关的环境线索而加速（Rohsenow等，1990），是可卡因成瘾治疗中最重要的障碍，和药物干预，破坏可卡因配对线索的急性激励作用或促进抑制性线索的建立-由于不利的脱靶效应和暂时/背景，没有药物关联在很大程度上是不成功的-依赖性治疗作用（综述见Torregrossa和Taylor，2016）。因此，FDA批准的可卡因成瘾药物仍然不可用。然而，新的治疗靶点，化合物和方法学进展的报告表明，正在朝着开发可卡因成瘾的有效疗法取得进展。其中一份报告由Monsey et al（2016）在最新一期的Neuropsychopharmacology中提供。在对大鼠进行的研究的基础上，作者提出了一种新的实验治疗方法，该方法可以损害可卡因记忆和随后的线索诱导的目标导向行为。适应不良联想的长期记忆可以被削弱的观点是Nader等人（2000）提出的记忆再巩固假说的推论。他们假设恐惧记忆在恢复时不稳定，必须经历一个依赖于蛋白质合成的重新巩固过程，以便随着时间的推移而保持。此外，根据最近的文献，药物记忆经历类似的再巩固过程，并且在药物记忆不稳定后应用的再巩固抑制剂操作破坏了药物复发动物模型中随后的巴甫洛夫可卡因条件反应和工具性目标导向行为（综述参见埃尔南德斯和Kelley，2005;索尔格，2012; García-Pardo et al，2016）Monsey et al（2016）的研究表明，Garcinol（一种聚异戊二烯化二苯甲酮衍生物）破坏可卡因记忆再巩固。在本研究中，在假定的可卡因记忆再巩固时间，即暴露于先前可卡因配对的条件刺激（CS）后30分钟，向大鼠全身给予加西酚。值得注意的是，Garcinol完全抑制随后的CS诱导的可卡因寻求行为和收购的一个新的CS加强反应的情况下，可卡因加固。Garcinol的作用依赖于外显CS记忆的再激活，并特异于再激活的CS-药物联想记忆。加辛未能抑制可卡因引发的可卡因寻求行为的恢复，因此一旦可卡因加入，它可能不会有太大的好处。这是意料之中的，因为可卡因引发和可卡因相关的线索可以通过不同的机制触发复发，需要单独解决。重要的是，加辛对线索诱导的恢复的抑制作用在以24天可卡因自我给药方案的形式进行更广泛的CS-可卡因训练后持续存在，并在2周强制戒断期后持续存在。Monsey et al（2016）的发现是重要的，因为令人遗憾的是，研究系统性操作对可卡因记忆再巩固的影响的研究由于多种原因尚未导致可行和有效的可卡因成瘾治疗。最...
According to the most recent US statistics,~ 15% of individuals aged 12 and older report having used cocaine at least once in their lifetime (National Survey on Drug Use and Health, 2015), and cocaine continues to be the most frequently cited drug of abuse during drug-related emergency room visits (Drug Abuse Warning Network, 2014). Relapse, frequently precipitated by exposure to drug-associated environmental cues (Rohsenow et al, 1990), is the most significant impediment in the treatment of cocaine addiction, and pharmacological interventions that disrupt the acute motivational effects of cocaine-paired cues or facilitate the establishment of inhibitory cue-no drug associations have been largely unsuccessful due to unfavorable off-target effects and temporary/context-dependent therapeutic effects, respectively (for review, see Torregrossa and Taylor, 2016). Thus, FDA-approved medications for cocaine addiction remain unavailable. However, reports of novel therapeutic targets, compounds, and methodological advances suggest that progress is being made toward the development of effective therapies for cocaine addiction. One such report is offered by Monsey et al (2016) in the current issue of Neuropsychopharmacology. On the basis of research conducted in rats, the authors propose a novel experimental treatment that impairs cocainecue memories and subsequent cue-induced goal-directed behavior. The idea that the long-term memories of maladaptive associations can be weakened is a corollary of the memory reconsolidation hypothesis proposed by Nader et al(2000). They postulated that fear memories destabilize upon retrieval and must undergo a protein synthesis-dependent reconsolidation process in order to be maintained over time. Furthermore, according to more recent literature, drug memories undergo a similar reconsolidation process, and reconsolidation inhibitor manipulations applied following drug memory destabilization disrupt subsequent Pavlovian cocaine-conditioned responses and instrumental goal-directed behaviors in animal models of drug relapse (for review, see Hernandez and Kelley, 2005; Sorg, 2012; García-Pardo et al, 2016).The study by Monsey et al(2016) indicates that garcinol, a polyisoprenylated benzophenone derivative, disrupts cocaine memory reconsolidation. In the study, garcinol was systemically administered to rats at the putative time of cocaine memory reconsolidation, 30min after exposure to the previously cocaine-paired conditioned stimuli (CS). Remarkably, garcinol completely inhibited subsequent CS-induced cocaine-seeking behavior and the acquisition of a new CS-reinforced response in the absence of cocaine reinforcement. The effects of garcinol were dependent on explicit CS memory reactivation and specific to the reactivated CS-drug associative memory. Garcinol failed to inhibit cocaine-primed reinstatement of cocaine-seeking behavior, and thus it may not be of much benefit once cocaine is on board. This was to be expected, given that cocaine priming and cocaine-associated cues can trigger relapse through different mechanisms that need to be addressed individually. Importantly, the inhibitory effects of garcinol on cue-induced reinstatement endured following more extensive CS-cocaine training in the form of a 24-day cocaine self-administration regimen and persisted after a 2-week forced abstinence period. Monsey et al(2016) findings are significant because, disappointingly, research examining the effects of systemic manipulations on cocaine memory reconsolidation has not yet led to feasible and efficacious treatments for cocaine addiction for a number of reasons. Most …