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，对社会有重大的经济和社会影响。一旦人们停止吸烟或饮酒，他们重新开始吸烟是很常见的。只有几种药物可以帮助防止患者重新启动，而且它们的效果有限。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，这往往会阻碍人们尝试戒烟，并可能抵消戒烟带来的健康益处。因此，防止体重增加和重新开始吸烟的药物将是最受欢迎的。增加重新开始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快感；(Ii)强迫症，即反复做同样的事情，无法抑制自己服用药物；(Iii)冲动，想要东西早而不晚，从事危险行为；以及(Iv)对压力环境更加敏感。这些行为相互作用，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。使用功能核磁共振和计算机任务的新的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，我们最近开发了一系列复杂的此类测试，调查酒精、可卡因和海洛因滥用者如何通过阻断特定大脑通路的药物(如多巴胺)来帮助他们。这些测试包括赢钱或赌钱，观看食物、药物或令人不快的压力图片，试图停止重复的运动，以及记忆力和选择力的测试。这项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来改变上瘾时的这些行为，方法是瞄准与食欲有关的肠道激素。人们早就知道，大脑处理酒精、滥用药物和食物的过程中也涉及到类似的区域。几种治疗成瘾的药物已经在帮助肥胖患者减肥和防止暴饮暴食方面有了一些好处。当我们进食时，肠道会改变血液中荷尔蒙的释放，向大脑发出信号，告诉大脑我们最后一次吃了多少，什么时候吃，从而减少饥饿，增加饱腹感。这些包括来自胃的激素酰基胃促生长素水平的下降和来自肠道的激素GLP-1的增加。基于这些激素的药物已经可用或正在开发中，以治疗肥胖症和糖尿病。胃肠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。最近在动物身上的研究发现，胃促生长素增加，GLP-1减少酒精、尼古丁和其他滥用药物的摄入量。这增加了它们可能成为治疗人类成瘾和防止人们戒烟或饮酒后复发的目标的可能性。它们还会有帮助减肥的额外好处。我们提议的研究将首次在人类身上调查这种影响，方法是在不同的日子注射不同的激素或假水，并通过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，我们的成瘾中的肠道激素(GHADD)研究将在健康的成年人和最近停止吸烟和酗酒的人中进行调查，如果降低/阻断酰基生长激素或给予胃肠激素GLP-1是否减少了对奖励敏感、冲动、强迫症和对负面情绪的反应的行为，以及这两种治疗方法是否都减少了对高热量食物的欲望和食欲。这项研究的结果将使临床研究取得进展，即模仿这些激素的作用的药物是否可以防止人们在戒烟或酗酒后复发，并解释它们是如何起作用的。

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.