̽��ֱ�� of Cambridge - David Belin

Highway to addiction: how drugs and alcohol can hijack your brain

cjb250 — Thu, 25 Feb 2016 15:14:44 +0000

There is a road down which those with substance addiction travel. Its beginnings are influenced by circumstances and genetics; it becomes well trodden, habitual, initially reinforced by pleasurable effects and then by cues; and, for some, it will become a road they can never leave.

Addiction is a chronic, relapsing psychiatric disease, with complex behavioural processes and equally complex changes to brain circuits. ̽��ֱ��brain of a person who has drunk alcohol or taken drugs is different to the brain of one who has not, as pharmacologist Dr David Belin describes: “I like whisky. I started drinking whisky when I was 20 and I have only a small amount now and then. But if I were to scan my brain, it changed that very first time, and it continues to be changed.”

And because drugs change the brain in ways that foster compulsive drug and alcohol abuse, quitting is difficult, even for those who want to. Belin and Professor Barry Everitt, from the Department of Pharmacology, have shown that some are more vulnerable than others to developing addiction – and to relapsing.

Their recent research, published in Nature Communications, uncovers a new neural ‘short cut’, or ‘back door’, in rat brains that could explain why some cocaine addicts relapse without intending to. ̽��ֱ��results, they believe, could suggest new forms of behavioural and pharmacological therapies.

A decade ago, both Belin and Everitt, independently, were the first to show that addiction manifests itself differently in different individuals and that, for some, compulsive cocaine-seeking behaviour would continue despite adverse circumstances. In a rat model, around 20% of animals addicted to cocaine still sought the drug despite the risk of receiving mild electric shocks on doing so.

“This was the first time in the field of addiction that the idea of inter-individual differences in vulnerability to compulsive drug seeking was raised,” explains Belin, who is funded by the Wellcome Trust. “With regard to psychiatric disorders, we are not equally vulnerable.”

Drug addiction had largely been regarded as the end point of a progressive loss of control over drug seeking resulting from a failure of part of the brain – the prefrontal cortex – that deals with decision making.

“Certainly, chronic exposure to drugs alters the prefrontal cortex, which governs motivation, inhibitory control and choice. But it also alters an area of the brain called the basolateral amygdala, which is associated with the link between a stimulus and an emotion,” explains Belin.

To explain further he gives the example of choosing to eat a cake or an apple. “ ̽��ֱ��basolateral amygdala stores the pleasurable memories associated with eating the cake, but the prefrontal cortex manipulates this information, helping you to weigh up whether or not you should eat another slice or choose the apple instead. If you eat the slice, regions of the ventral striatum, the structure that processes reward and links emotions to actions, are activated.”

However, Belin and Everitt’s latest research has shown that this is not the only neuronal circuit that underlies cocaine-seeking behaviour.

Using their rat model, they identified a completely new highway that links impulses with habits. This brain circuit links the basolateral amygdala indirectly with the dorsolateral striatum, which is the neural locus of habits.

“Because it doesn’t recruit the prefrontal cortex it doesn’t involve choice,” explains Belin. “It’s a short cut or back door directly to habit. It means that addicts can have internal urges they are not aware of that drive drug seeking. It’s a newly recognised function of this brain circuitry.

“It would explain situations in which individuals who have been abstinent for five years suddenly relapse, telling their counsellor ‘I was walking in the street and I found myself with a glass of wine – and I promise you I didn’t want it.’ This has often been dismissed as ‘weakness of the will’ and then denial. This may also happen, but what our results in rats suggest is that there are occasions in which the stimuli go via motivation straight to the habit part of the brain without an individual even being aware of it.”

̽��ֱ��researchers believe that this is a breakthrough in understanding how drugs like cocaine can hijack the brain with such devastating consequences. “We can speculate that the subset of individuals currently using drugs who are especially vulnerable to addiction might have a stronger pathway – a ‘superhighway’ to habit formation.”

̽��ֱ��finding could explain the puzzling feature of why substance abusers repeatedly do something they know is bad for them. This is an area that interests Dr Valerie Voon in the Department of Psychiatry. “There appears to be a form of impulsivity called ‘waiting impulsivity’ that doesn’t involve choice and that predisposes to drug addiction.”

Waiting impulsivity is seen when a runner takes off before the starter pistol, or when someone interrupts inappropriately. Voon has devised a way of measuring it in humans based on tasks studied in rats. She also uses another task that teases apart decisions that are made through choices that are goal directed (i.e. taking into account the goal or outcome) from those that are habitual (i.e. relying rather automatically on past rewarding choices).

“We find that alcohol addiction correlates with waiting impulsivity. Once you’re abstinent, the compulsivity or habits also improve. Now that we have this test we can start to cut across other addictions – is there an underlying neural process shared by all? Can we ascribe causality? Can we suggest new treatments?”

Belin suggests that a combination of behavioural and pharmacological treatments might be the answer to helping addicts quit.

Treatments such as cognitive behavioural therapy aim to restore the function of the prefrontal cortex so that emotions don’t automatically elicit habits. “But if people are not aware of their impulses then they can’t subjectively or cognitively apprehend the motivation and the impulse to take drugs or drink,” says Belin. “It’s possible that mindfulness might be beneficial in helping them identify the impulses.”

Although there is currently no effective pharmacological treatment for cocaine addiction, his team has recently shown that N-acetylcysteine might be a possibility, but only if used early enough on the road to addiction when the individual still has the motivation to stop.

̽��ֱ��researchers now plan to extend their study of cocaine addiction to compulsive alcohol- and heroin-seeking behaviour. They and Voon would like to understand to what degree behavioural traits such as impulsivity, novelty preference and anxiety – using brain imaging to identify neural correlates – can be used as a predictor of compulsive drug seeking.

“Drug taking is always volitional to begin with – you take drugs because you want to experience something,” adds Belin. “Unfortunately they hijack the learning mechanisms in your brain so that you don’t really take them because you want them but because stimuli in your environment tell you to do so. We want to work out how we can help people become aware that their impulses are wrongly triggering their habits.”

̽��ֱ��discovery of a brain circuit ‘shortcut’ could explain why some addicts unintentionally relapse, and suggests that a shift in focus for therapies might help those who want to stay off drugs.

I started drinking whisky when I was 20 and I have only a small amount now and then. But if I were to scan my brain, it changed that very first time, and it continues to be changed

David Belin

̽��ֱ��District

Highway to addiction

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Cocaine addiction: Scientists discover ‘back door’ into the brain

cjb250 — Tue, 12 Jan 2016 00:17:37 +0000

A second study from the team suggests that a drug used to treat paracetamol overdose may be able to help individuals who want to break their addiction and stop their damaging cocaine seeking habits.

Although both studies were carried out in rats, the researchers believe the findings will be relevant to humans.

Cocaine is a stimulant drug that can lead to addiction when taken repeatedly. Quitting can be extremely difficult for some people: around four in ten individuals who relapse report having experienced a craving for the drug – however, this means that six out of ten people have relapsed for reasons other than ‘needing’ the drug.

“Most people who use cocaine do so initially in search of a hedonic ‘high’,” explains Dr David Belin from the Department of Pharmacology at the ̽��ֱ�� of Cambridge. “In some individuals, though, frequent use leads to addiction, where use of the drug is no longer voluntary, but ultimately becomes a compulsion. We wanted to understand why this should be the case.”

Drug-taking causes a release in the brain of the chemical dopamine, which helps provide the ‘high’ experienced by the user. Initially the drug taking is volitional – in other words, it is the individual’s choice to take the drug – but over time, this becomes habitual, beyond their control.

Previous research by Professor Barry Everitt from the Department of Psychology at Cambridge showed that when rats were allowed to self-administer cocaine, dopamine-related activity occurred initially in an area of the brain known as the nucleus accumbens, which plays a significant role driving ‘goal-directed’ behaviour, as the rats sought out the drug. However, if the rats were given cocaine over an extended period, this activity transferred to the dorsolateral striatum, which plays an important role in habitual behaviour, suggesting that the rats were no longer in control, but rather were responding automatically, having developed a drug-taking habit.

̽��ֱ��brain mechanisms underlying the balance between goal-directed and habitual behaviour involves the prefrontal cortex, the brain region that orchestrates our behaviour. It was previously thought that this region was overwhelmed by stimuli associated with the drugs, or with the craving experienced during withdrawal; however, this does not easily explain why the majority of individuals relapsing to drug use did not experience any craving.

Chronic exposure to drugs alters the prefrontal cortex, but it also alters an area of the brain called the basolateral amygdala, which is associated with the link between a stimulus and an emotion. ̽��ֱ��basolateral amygdala stores the pleasurable memories associated with cocaine, but the pre-frontal cortex manipulates this information, helping an individual to weigh up whether or not to take the drug: if an addicted individual takes the drug, this activates mechanisms in the dorsal striatum.

However, in a study published today in the journal Nature Communications, Dr Belin and Professor Everitt studied the brains of rats addicted to cocaine through self-administration of the drug and identified a previously unknown pathway within the brain that links impulse with habits.

̽��ֱ��pathway links the basolateral amygdala indirectly with the dorsolateral striatum, circumventing the prefrontal cortex. This means that an addicted individual would not necessarily be aware of their desire to take the drug.

“We’ve always assumed that addiction occurs through a failure or our self-control, but now we know this is not necessarily the case,” explains Dr Belin. “We’ve found a back door directly to habitual behaviour.

“Drug addiction is mainly viewed as a psychiatric disorder, with treatments such as cognitive behavioural therapy focused on restoring the ability of the prefrontal cortex to control the otherwise maladaptive drug use. But we’ve shown that the prefrontal cortex is not always aware of what is happening, suggesting these treatments may not always be effective.”

In a second study, published in the journal Biological Psychiatry, Dr Belin and colleagues showed that a drug used to treat paracetamol overdose may be able to help individuals addicted to cocaine overcome their addiction – provided the individual wants to quit.

̽��ֱ��drug, N-acetylcysteine, had previously been shown in rat studies to prevent relapse. However, the drug later failed human clinical trials, though analysis suggested that while it did not lead addicted individuals to stop using cocaine, amongst those who were trying to abstain, it helped them refrain from taking the drug.

Dr Belin and colleagues used an experiment in which rats compulsively self-administered cocaine. They found that rats given N-acetylcysteine lost the motivation to self-administer cocaine more quickly than rats given a placebo. In fact, when they had stopped working for cocaine, they tended to relapse at a lower rate. N-acetylcysteine also increased the activity in the brain of a particular gene associated with plasticity – the ability of the brain to adapt and learn new skills.

“A hallmark of addiction is that the user continues to take the drug even in the face of negative consequences – such as on their health, their family and friends, their job, and so on,” says co-author Mickael Puaud from the Department of Pharmacology of the ̽��ֱ�� of Cambridge. “Our study suggests that N-acetylcysteine, a drug that we know is well tolerated and safe, may help individuals who want to quit to do so.”

Reference
Murray, JE et al. Basolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits. Nature Comms; 16 December 2015

Ducret, E et al. N-acetylcysteine facilitates self-imposed abstinence after escalation of cocaine intake. Biological Psychiatry; 7 Oct 2015

Individuals addicted to cocaine may have difficulty in controlling their addiction because of a previously-unknown ‘back door’ into the brain, circumventing their self-control, suggests a new study led by the ̽��ֱ�� of Cambridge.

Most people who use cocaine do so initially in search of a hedonic ‘high’. In some individuals, though, frequent use leads to addiction, where use of the drug is no longer voluntary, but ultimately becomes a compulsion

David Belin

D. Sinclair Terrasidius

relaxing after work_MMVI (cropped)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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