Do appetitive gut hormones attenuate core behavioural components of addiction to prevent relapse in nicotine and alcohol addiction?

吸烟和酗酒是主要的健康负担，对社会造成重大的经济和社会影响。一旦人们停止吸烟或饮酒，他们通常会重新开始。只有少数药物可以帮助防止人们重新开始，而且它们的成功率有限。需要新的目标和更有效的药物。人们戒烟后的另一个问题是，他们通常会增加体重，这往往会阻碍人们戒烟，并可能抵消戒烟带来的健康益处。因此，既能防止体重增加又能防止重新吸烟的药物是最受欢迎的。增加重新吸烟或饮酒的风险的行为包括：（i）对药物的渴望增加或从服用药物中获得更大的乐趣;（ii）强迫性，即反复做同样的动作，无法抑制自己服用药物;（iii）强迫性，即无法抑制自己服用药物。（iii）易冲动，希望事情越快越好，以及从事冒险行为;及（iv）对压力环境的敏感性增加。这些行为相互影响，涉及几个重叠的大脑区域的协调活动，包括额叶，杏仁核，背侧和腹侧纹状体。使用功能性MRI和计算机任务的新大脑成像技术可以测量这些行为和相关的大脑激活。作为MRC资助的ICCAM项目的一部分，我们最近开发了一种复杂的测试选择，调查酒精，可卡因和海洛因滥用的人如何通过阻断特定大脑通路的药物（如多巴胺）获得帮助。这些测试包括赢钱或赌钱，看食物、药物或令人不快的压力图片，试图停止重复的动作，以及记忆和选择测试。目前的提议将使用一系列相同的测试来研究一种全新的方法，通过靶向肠道中与食欲有关的激素来改变成瘾中的这些行为。人们早就知道，类似的区域参与大脑对酒精、滥用药物和食物的处理。几种用于治疗成瘾的药物对减肥和防止暴饮暴食有一定的好处。当我们吃东西时，肠道会改变激素释放到血液中，向大脑发出信号，告诉我们上次吃了多少和什么时候吃，以减少饥饿感并增加饱腹感。这些包括胃中酰基生长激素释放肽水平的福尔斯下降和肠中GLP-1激素水平的增加。基于这些激素的药物可用于或正在开发中以治疗肥胖和糖尿病。肠道激素还通过对大脑奖励系统的作用来改变食物的愉悦程度。最近对动物的研究发现，生长激素释放肽增加，GLP-1减少酒精、尼古丁和其他滥用药物的摄入。这增加了它们可能成为治疗人类成瘾和防止人们停止吸烟或饮酒后复发的目标的可能性。他们也将有额外的好处，帮助减肥。我们提出的研究将首次通过在不同的日子施用不同的激素或虚拟水注射来研究人类的这种影响，并使用这些大脑成像和计算机任务来观察它们对成瘾行为的影响。因此，我们的成瘾性肠道激素（GHADD）研究将在健康成年人和最近戒烟和酗酒的人中进行调查，如果降低/阻断酰基生长激素释放肽或给予肠道激素GLP-1可以减少奖励敏感性，冲动性，强迫性和对负面情绪的反应，如果任何一种治疗方法都能降低对高血压的渴望，这项研究的结果将使临床进展，是否药物模仿这些激素的作用，防止复发后，人们停止吸烟或酗酒，并解释他们是如何工作的。

Smoking and alcohol abuse are major health burdens, with significant economic and social impacts on society. Once people stop smoking or drinking alcohol it is common for them to restart. There are only a few medications to help prevent people restarting, and they have limited success. New targets and more effective medications are needed. An additional problem after people stop smoking is that they commonly gain weight, which often hinders people trying to stop smoking, and can undo the health benefits gained by stopping smoking. Medications that prevent both weight gain and restarting smoking would therefore be most welcome.Behaviours that increase the risk of relapse to restarting smoking or drinking alcohol include: (i) increased craving for a drug or getting greater pleasure from taking it; (ii) being compulsive, that is doing the same actions repeatedly and being unable to inhibit oneself taking the drug; (iii) being impulsive, wanting things sooner rather than later, and engaging in risky behaviour; and (iv) increased sensitivity to stressful circumstances. These behaviours interact with each other, and involve co-ordinated activity of several overlapping brain regions including the frontal lobes, amygdala, dorsal and ventral striatum. New brain imaging techniques using functional MRI and computer tasks can measure these behaviours and associated brain activation. We have recently developed a sophisticated selection of such tests, as part of the MRC-funded ICCAM project, investigating how people with alcohol, cocaine and heroin abuse, may be helped by medications that block specific brain pathways e.g. dopamine. The tests involve winning or gambling money, looking at food, drug or unpleasant stressful pictures, trying to stop repetitive movements, and tests of memory and choice.This current proposal will use an identical series of tests to investigate a completely new way of modifying these behaviours in addiction by targeting hormones from the gut that are involved in appetite. It has long been known that similar regions are involved in the brain's processing of alcohol, drugs of abuse and food. Several drugs developed to treat addiction have had some benefits to help with weight loss in obesity and prevent binge eating. When we eat, the gut changes the release of hormones into the blood to signal to the brain how much and when we last ate, to reduce hunger and increase fullness. These include falls in the levels of the hormone acyl ghrelin from the stomach and increases in the hormone GLP-1 from the intestine. Medications based on these hormones are available or in development to treat obesity and diabetes. Gut hormones also alter how pleasurable food is to eat through actions on brain reward systems.Recently studies in animals have found that ghrelin increases and GLP-1 decreases the intake of alcohol, nicotine and other drugs of abuse. This raises the possibility that they may be targets to treat human addiction and prevent relapse after people stop smoking or drinking alcohol. They would also have the added benefit of aiding weight loss. Our proposed study will investigate such effects in humans for the first time by administering differing hormones or a dummy water injection on different days and seeing their effects on addictive behaviours using these brain imaging and computer tasks. Our Gut Hormones in ADDiction (GHADD) study will therefore investigate in healthy adults and those who have recently stopped smoking and abusing alcohol, if lowering/blocking acyl ghrelin or giving the gut hormone GLP-1 reduces the behaviours of reward sensitivity, impulsivity, compulsivity, and responses to negative emotions, and if either treatment reduces the desire for high-calorie foods and appetite.The results of this study will enable progress to clinical of whether drugs mimicking the actions of these hormones prevent relapse after people stop smoking or abusing alcohol, and explain how they work.