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适应不良行为变化反映了神经元和突触水平的可塑性。一般来说，稳定形式的可塑性需要蛋白质合成，即使是弱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，行为和突触，可以破坏形成稳定的竞争协会，这种破坏增强蛋白质合成时，促进。具体来说，我们预测，糖原合成酶激酶3（GSK 3），通过增加神经元的合成能力，促进蛋白质合成的抑制剂，将促进可卡因诱导的可塑性的逆转，减少药物寻求行为。具体目标。行为和电生理学研究将用于解决两个具体目标：-GSK3抑制剂是否降低了以前被教导自我施用可卡因的大鼠在灭绝后恢复药物寻求行为的可能性？- GSK3抑制剂是否有助于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GSK 3抑制剂作为药物成瘾治疗开辟道路，它们将增强认知疗法在扰乱寻药行为方面的有效性。与NIDA的使命有关。药物渴望和复吸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药物上瘾的美国人的结果。成瘾和突触可塑性基础研究的重要性。压倒性的证据表明腹侧被盖区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，对药物诱导的可塑性的可逆性知之甚少。这一建议将阐明这些领域，以及GSK 3在控制新成立协会的稳定性方面的作用。实验设计和方法总结。将使用从其大脑制备的切片，研究接受过自我施用可卡因训练的大鼠（在主动杠杆按压时进行药物递送，与提示光的呈现相关）的腹侧被盖区可塑性。在其他大鼠中，我们将在存在或不存在GSK3抑制剂的情况下消除VTA压迫行为，然后我们将测试动物恢复VTA压迫（药物寻求行为）的可能性，或者我们将处死动物以确定VTA中可卡因诱导的可塑性是否逆转。 公共卫生相关性：可卡因和其他成瘾性药物会对大脑中评估刺激和体验的奖励价值的区域产生非常持久和有害的变化。我们在行为和生理水平上对这些改变的理解的提高，以及对其破坏的可能方法的识别，将导致新的治疗方法，以减少药物滥用者复发的可能性。在这个项目中，我们将探索逆转可卡因诱导的大鼠行为影响的可能性，以及评估刺激和经验的奖励价值的大脑区域的突触功能。

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.