The reconsolidation of instrumental cocaine-seeking memories

可卡因等非法药物成瘾具有重要的社会经济和健康后果，2000年在联合王国造成的总成本估计为120亿英镑。因此，提高戒断吸毒的策略是非常需要的。成瘾性药物是强有力的奖励，其作用方式与食物等自然奖励非常相似。因此，成瘾的特点是将药物与药物相关线索和药物寻求行为的工具反应联系起来的强烈记忆。这两种记忆对于长期寻求毒品的行为都很重要。因此，减少这些药物相关记忆的策略可能是一种支持戒断/抗复发的治疗方法。记忆重新巩固的现象提供了一个潜在的机会来破坏现有的记忆，包括提示药物和反应药物记忆。当一段记忆被提取出来时，它有时会进入一个被称为“重新巩固”的过程，这是记忆在此后持续存在所必需的。如果再巩固过程被打乱，记忆就会被打乱。我们之前在一个大鼠模型中证明，线索食物和线索可卡因的记忆可以以这种方式中断，导致线索诱导的食物和可卡因寻找的部分减少。此外，我们最近有证据表明，反应性食物记忆也会经历再巩固。重要的是，以重新巩固为基础的治疗已经被应用于人类创伤后应激障碍患者，因此在药物成瘾方面确实有可能产生有益的效果。然而，在翻译相关的啮齿动物模型中，仍然需要证明，工具反应-可卡因记忆的重新巩固可以被破坏以减少可卡因寻求。上瘾复发的主要原因有三个。这些是暴露于药物相关线索，暴露于药物本身，暴露于压力。以往大多数关于成瘾性药物背景下记忆再巩固的研究都集中在通过靶向线索药物记忆的线索诱导复发上。然而，几乎没有证据表明药物诱导和应激诱导的复发可以通过基于线索药物记忆再巩固的治疗来减少。考虑到药物寻求对记忆的基本依赖，即工具性反应提供了对药物的访问，可以预期，反应-药物记忆再巩固的损害将减少各种形式的复发。因此，目前的项目主要集中在基于工具再巩固治疗的药物寻求复发的潜在应用，并将提出两个主要问题：1。工具性反应-可卡因记忆的再巩固是否会被破坏？对工具性反应-可卡因记忆再巩固的破坏对减少线索诱导、药物诱导和压力诱导的复发有效吗？为了回答这些问题，并测试我们的特定假设，我们将主要使用行为测试（在行为自由的大鼠中进行行为药理学分析），并添加与记忆再巩固相关的分子变化分析。假设的性质和检验方法需要使用实验动物。老鼠是最没有知觉的物种，它与人类保持着一定程度的生物相似性，因此我们的结论可以合理地应用于对人类学习和记忆的理解。

Addiction to illicit drugs, such as cocaine, has important socio-economic and health consequences, causing an estimated total cost of £12 billion in the UK in 2000. Therefore, strategies to improve abstinence from drug taking are highly desired. Addictive drugs are powerful rewards, acting in much the same way as natural rewards such as food. As such, addiction is characterised by strong memories that link the drug to both drug-related cues and to the instrumental responses in drug seeking behaviour. Both of these memoryies are important in perpetuating drug-seeking behaviour. Therefore strategies to diminish these drug-associated memories would be potentially useful as a pro-abstinence/anti-relapse treatment.The phenomenon of memory reconsolidation provides a potential opportunity to disrupt existing memories, including cue-drug and response-drug memories. When a memory is retrieved, it sometimes enters into a process termed "reconsolidation", which is necessary for the memory to persist thereafter. If the reconsolidation process is disrupted, the memory is disrupted. We have previously demonstrated in a rat model that cue-food and cue-cocaine memories can be disrupted in this manner, leading to a partial reduction in cue-induced food- and cocaine-seeking. Moreover, we have recent evidence that response-food memories also undergo reconsolidation. Importantly, reconsolidation-based treatments are already being translated to human post-traumatic stress disorder patients, and so there is a real possibility of beneficial effects in drug addiction. However, it remains to be demonstrated that the reconsolidation of instrumental response-cocaine memories can be disrupted to reduce cocaine seeking in translationally-relevant rodent models.There are three main causes of relapse in addiction. These are exposure to the drug-associated cues, exposure to the drug itself, and exposure to stress. Most previous studies of memory reconsolidation in addictive drug settings have focussed on cue-induced relapse by targeting cue-drug memories. However, there is little evidence that drug-induced and stress-induced relapse can be reduced by cue-drug memory reconsolidation-based treatments. Given the fundamental dependence of drug seeking upon the memory that the instrumental response gives access to the drug, it would be expected that an impairment in response-drug memory reconsolidation will reduce all manners of relapse. Therefore, the current project is focussed upon the potential application of instrumental reconsolidation-based treatments for relapse to drug seeking, and will ask 2 main questions: 1. Can the reconsolidation of instrumental response-cocaine memories be disrupted?2. Is the disruption of instrumental response-cocaine memory reconsolidation effective at reducing cue-induced, drug-induced and stress-induced relapse?In order to answer these questions, and test our specific hypotheses, we will primarily use behavioural testing (behavioural pharmacological analyses in freely behaving rats), with the addition of analyses of molecular changes that are associated with memory reconsolidation. The nature of the hypotheses and the approaches needed to test them require the use of experimental animals. Rats are the least sentient species that retain a level of biological similarity to humans such that our conclusions can reasonably be applied to the understanding of human learning and memory.