Characterising the effects of chronic opioid use on regulatory control and the development of compulsivity in heroin addiction.

吸毒成瘾是一个造成重大危害的重大公共卫生问题。阿片剂是市场上最容易上瘾的药物之一，处方类阿片的使用日益增多，导致全世界阿片剂成瘾率急剧上升。虽然在欧洲，阿片剂成瘾的人数相对稳定，但毒品市场不断扩大，合成类阿片在互联网上的供应日益增加，这是一个日益令人关切的问题，使阿片剂成瘾的治疗比以往任何时候都更加紧迫。然而，没有理论上有原则的治疗策略，其针对阿片类药物成瘾发展的神经生物学机制。目前治疗的主流仍然是替代疗法，即用美沙酮等长效类阿片替代海洛因等短效类阿片。替代疗法在实现长期戒断方面的疗效有限，因为成瘾者倾向于增加他们的替代处方将非法阿片类药物。至关重要的是，替代疗法并不治疗成瘾者的适应不良行为;相反，尽管对使用者的健康产生了负面影响，但这种行为仍然存在。动物研究表明，长期使用阿片类药物扰乱了与行为调节有关的大脑系统，从而使行为变得僵硬，损害了患者认识其行为后果的能力。然而，这些发现主要来自多巴胺能兴奋剂药物的研究，而阿片类药物对行为控制的影响仍然知之甚少。在这里，我们提出了一项研究，以检查与慢性阿片类药物使用相关的监管控制系统的变化，以确定阿片类药物强迫使用的机制。我们将检查三组个体：一组是处方阿片类药物作为阿片类药物成瘾的替代治疗，另一组是处方阿片类药物治疗慢性疼痛（非成瘾），另一组是以前没有阿片类药物经验的健康个体。该研究的主要目标是评估定期使用阿片类药物对习惯形成和目标导向学习的影响，这些影响使用选择性神经认知任务，这些任务是基于动物模型开发的。第二个目标是使用神经成像技术来研究功能相互作用的皮层和皮层下区域的神经网络（无论是在挑战和休息时），以提供支持异常习惯形成的大脑系统的信息。这些见解将为吸毒成瘾研究带来重要的科学进展，并将对制定治疗和/或预防干预措施至关重要，这些干预措施旨在针对个人对行为改变的抵制，尽管会产生负面后果。它还将提供概念验证，以支持未来的研究，调查阿片类药物成瘾的风险和弹性标志物，我们计划成功完成这项研究。

Drug addiction is a major public health problem that causes significant harm. Opiates are one of the most addictive drugs on the market and the increasing use of prescription opioids contributed to the stark rise in the rates of opiate addiction worldwide. Although in Europe the numbers of people addicted to opiates have been relatively stable, the expanding drug markets and the increasing availability of synthetic opioids over the internet are a growing concern, rendering treatments of opiate addiction more pressing than ever before. Yet, there are no theoretically principled treatment strategies, which target the neurobiological mechanisms underlying the development of opioid addiction. The mainstay of current treatment is still substitution therapy, i.e. replacing short-acting opiates like heroin with longer-acting opioids like methadone. Substitution therapy only has limited efficacy in achieving long-term abstinence because addicted individuals tend to top up their substitution prescription will illicit opioids. Critically, substitution therapy does not treat the maladaptive behaviours of addicted individuals; on the contrary, the behaviour persists despite negative consequences for the users’ health. Animal studies suggest that chronic use of opiates disrupts brain systems implicated in the regulation of behaviour, thus rendering behaviour inflexible and impairing patients’ ability to appreciate the consequences of their actions. However, these findings largely derive from studies of dopaminergic stimulant drugs, whilst the effects of opioids on behavioural control are still poorly understood. Here we propose a study to examine the changes in regulatory control systems associated with chronic opiate use to identify the mechanisms underlying the compulsive use of opioids. We will examine three groups of individuals: one group who is prescribed opioids as a substitution treatment for opiate addiction, another one with prescribed opioids for chronic pain (non-addicted), and one of healthy individuals who have no prior experience with opioids. The primary goal of the study is to evaluate the effects of regular opioid use on habit formation and goal-directed learning using selective neurocognitive tasks, which have been developed based on animal models. The secondary goal is to use neuroimaging technology to investigate the neural network of functionally interacting cortical and subcortical regions (both when challenged and at rest) to provide information on brain systems underpinning abnormal habit formation. These insights will yield important scientific advances for drug addiction research and will be crucial for the development of therapeutic and/or preventative interventions designed to target individuals’ resistance to behaviour change despite negative consequences. It will also provide proof-of-concept to support future studies investigating markers of risk and resilience in opioid addiction, which we are planning to succeed this study.