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

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.

Smoking and alcohol abuse and dependence are major health burdens, with significant economic, social and societal impacts. Relapse after abstinence in substance and drug dependence is common and current treatments are limited. Novel therapeutic targets are needed to aid abstinence and prevent relapse through actions on the interacting core behavioural components in addiction.

Recent pre-clinical studies in rodents have demonstrated that circulating appetitive gut hormones, such as acyl ghrelin and glucagon-like peptide-1 (GLP-1), which vary with nutritional state, can influence not only appetite and food reward but also consumption of alcohol, nicotine and other drugs of abuse, through brain mesocorticolimbic dopaminergic and opioid systems. It is currently unknown whether these gut hormones can influence such behaviours in human addiction. Furthermore weight gain after smoking cessation, through increases in appetite and food reward, may attenuate health benefits, hinder attempts at abstinence and promote relapse.

Building on an established platform of functional MRI and behavioural tasks, the objectives of this Gut Hormones in ADDiction (GHADD) proof-of-concept experimental medicine study are to investigate, in abstaining adults with nicotine and alcohol dependence and healthy controls, whether:

(i) suppressing/antagonising the appetitive gut hormone acyl ghrelin attenuates core behavioural components of addiction, including reward sensitivity to cigarettes, alcohol and money, impulsivity/compulsivity including delay discounting and inhibitory motor responses, negative emotional salience;

(ii) administration of the anorexigenic gut hormone GLP-1 attenuates core behavioural components of addiction;

(iii) suppressing/antagonising acyl ghrelin or administering GLP-1 attenuates reward-hedonic responses to high-calorie foods and appetite.

This will provide evidence of the utility of and mechanisms behind these novel therapeutic targets for addiction.

There is a pressing need to develop novel pharmacotherapies for addiction and an approach derived from knowledge of brain mechanisms of relapse offers a way forward. Our study will use the experimental medicine research platform from the MRC-funded ICCAM study ("New drugs for addiction: focus on attenuating core behavioural components of heroin, cocaine and alcohol dependence"), investigating the role of dopaminergic and opioid pathways on reward sensitivity, stress / negative emotional salience, impulsivity and compulsivity.

Our study will incorporate a novel potential target for pharmacological treatments in addiction namely appetitive gut hormones. The influences of these hormones will be assessed using the established cognitive-fMRI paradigms addressing key relapse pathways in human addiction. This will establish if the influence of gut hormones acyl ghrelin and GLP-1 in addiction maps from animal models to humans in the major addiction disorder populations of alcohol and nicotine dependence. Demonstration that suppression/antagonism of acyl ghrelin and/or administration of GLP-1 alter any of these core behavioural components of addiction will provide proof-of-concept evidence to progress to clinical trial(s) with the relevant hormone and population.

Medications are already available to translate to intervention studies for the prevention of relapse after smoking cessation and alcohol abstinence. GLP-1 analogues (Exenatide, Liraglutide) are licensed for the treatment of diabetes, administered as daily/weekly subcutaneous injections. More stable desacyl ghrelin analogues such as cyclised DAG(6-13) derivatives (e.g. AZP531) that can be administered subcutaneously are also under development (e.g. Alize Pharma). The utility of such medications in the field of substance abuse will be ascertained from clinical trials focusing on both preventing relapse after a period of abstinence e.g. several months after initial alcohol detoxification, and aiding initial cessation by commencement coincident with stopping the drug e.g. cigarettes, either alone or in combination with other pharmaceutical agents such as nicotine replacement therapy.

Weight gain after smoking cessation, through increases in appetite and food reward, may attenuate health benefits, hinder attempts at abstinence and promote relapse. Use of these therapies under such circumstances may help prevent such weight gain and hence also indirectly attenuate relapse, as they reduce food reward and appetite. These drugs also improve glucose metabolism through actions on insulin release/sensitivity providing additional benefits in overweight/insulin-resistant patients, common co-morbidities in smokers and alcohol dependence.

In addition to these other beneficial effects of gut hormones, their action through replication of endogenous hormonal changes which occur regularly as we eat meals may also help avoid side effects seen with drugs targeting neurotransmitter systems. In the future experimental studies could also be extended to study patients still consuming drugs to see if it assists with commencement of abstinence, as well as prevention of relapse. Similarly they could study the effects on core behavioural components of addiction in opiate and stimulant abuse and dependency. Other anorexigenic gut hormones such as PYY3-36 have additive or synergistic anorexigenic effects with GLP-1 on appetite and brain food reward responses. It is not currently known if there are any effects of PYY3-36 on alcohol and drug of abuse reward and intake from preclinical studies. Furthermore drugs are not yet clinically available to target PYY3-36 signalling unlike GLP-1, though they are in development. As further preclinical reports are published these experimental paradigm can be extended to study other anorexigenic hormones such as PYY3-36 administration alone, or in combination with GLP-1 or desacyl ghrelin agonists, in alcohol and drug dependency.