Reversing Cocaine-Induced Plasticity with GSK3 Inhibitors

描述（由申请人提供）：与药物成瘾相关的持续的不适应行为改变反映了神经元和突触水平上的可塑性。一般来说，稳定的可塑性形式需要蛋白质合成，即使是微弱的事件也可以在蛋白质合成活跃的条件下产生持久的变化。我们假设药物诱导的可塑性，包括行为和突触，可以被稳定的竞争关联的形成所破坏，当蛋白质合成被促进时，这种破坏会增强。具体来说，我们预测糖原合成酶激酶3 （GSK3）的抑制剂，通过增加神经元的合成能力来促进蛋白质的合成，将促进可卡因诱导的可塑性的逆转，减少药物寻求行为。具体的目标。行为学和电生理学研究将用于解决两个特定的目标：- GSK3抑制剂是否会降低以前被教导自我使用可卡因的大鼠在灭绝后恢复寻求药物行为的可能性？GSK3抑制剂能否帮助逆转可卡因暴露在腹侧被盖区（VTA）诱导的突触可塑性？长期目标。如果获得积极的结果，这些研究将为开发GSK3抑制剂作为药物成瘾的治疗开辟道路，它们将增强认知疗法在破坏药物寻求行为方面的有效性。与NIDA的使命相关。对毒品的渴望和复发一直是治疗药物滥用中最难解决的问题，需要创新的方法来改善数百万对可卡因和其他毒品上瘾的美国人的结果。成瘾与突触可塑性基础研究的重要性。大量证据表明，VTA是药物成瘾的关键脑区，但对突触水平的药物成瘾机制仍知之甚少，对药物诱导可塑性的可逆性了解更少。该提案将阐明这些领域，以及GSK3在控制新形成的协会稳定性方面的作用。实验设计和方法总结。研究人员将使用从大鼠大脑中提取的薄片，研究自我使用可卡因的大鼠（在主动按压杠杆的情况下给药，并伴有提示光的呈现）的VTA可塑性。在其他大鼠中，我们将在GSK3抑制剂存在或不存在的情况下消除压杆行为，然后我们将测试动物返回压杆（寻求药物行为）的可能性，或者我们将牺牲动物以确定可卡因诱导的VTA可塑性是否被逆转。

DESCRIPTION (provided by applicant): The persistent maladaptive behavioral changes that are associated with drug addiction reflect plasticity at the level of neurons and synapses. In general, stable forms of plasticity require protein synthesis, and even weak events can produce long-lasting changes under conditions where protein synthesis is active. We hypothesize that drug-induced plasticity, both behavioral and synaptic, can be disrupted by the formation of stable competing associations, and this disruption is enhanced when protein synthesis is facilitated. Specifically, we predict that inhibitors of glycogen synthetase kinase 3 (GSK3), which facilitate protein synthesis by increasing the synthetic capacity of neurons, will promote the reversal of cocaine-induced plasticity and reduce drug-seeking behavior. Specific aims. Behavioral and electrophysiological studies will be used to address two specific aims: - Do GSK3 inhibitors reduce the likelihood that rats who were previously taught to self-administer cocaine will return to drug-seeking behavior after extinction? - Can GSK3 inhibitors help to reverse the synaptic plasticity that is induced in the ventral tegmental area (VTA) by cocaine exposure? Long-term objectives. If positive results are obtained, these studies will open the way to developing GSK3 inhibitors as a treatment for drug addiction, where they would enhance effectiveness of cognitive therapy in disrupting drug-seeking behavior. Relevance to NIDA's mission. Drug craving and relapse have been the most difficult problems to solve in treating drug abuse, and innovative approaches are required to improve the outcome for the millions of Americans who are addicted to cocaine and other drugs. Importance to basic research on addiction and synaptic plasticity. Overwhelming evidence points to the VTA as a key brain region in drug addiction, but the mechanism of drug addiction at the synaptic level remains poorly understood, and even less is known about the reversibility of drug-induced plasticity. This proposal will shed light on those areas, and on the role of GSK3 in controlling the stability of newly-formed associations. Summary of experimental design and methods. Rats trained to self-administer cocaine (drug delivery upon active lever pressing, associated with presentation of cue light) will be studied with regard to plasticity in the VTA, using slices prepared from their brains. In other rats, we will extinguish the lever-pressing behavior in the presence or absence of a GSK3 inhibitor, and later we will either test how likely the animals are to return to lever-pressing (drug-seeking behavior), or we will sacrifice the animals to determine if cocaine-induced plasticity in the VTA was reversed. PUBLIC HEALTH RELEVANCE: Cocaine and other addictive drugs produce very persistent and detrimental changes to regions of the brain that evaluate the reward value of stimuli and experiences. Improvements in our understanding of these modifications at the behavioral and physiological levels, and the identification of possible methods for their disruption, will lead to new therapies to reduce the likelihood of relapse in drug abusers. In this project, we will explore the possibility of reversing cocaine-induced effects on behavior in rats trained to self-administer cocaine, and on synaptic function in a brain area that evaluates the reward value of stimuli and experiences.