At the British Neuroscience Association (BNA)’s Festival of Neuroscience in April 2019, we were lucky enough to sit down with some influential neuroscientists to discuss their work. We’ve assembled these transcripts into our BNA Interview Series. Here, we interview Cambridge University's Professor Barry Everitt on the connections between neural systems of learning and memory, and the compulsions and behaviors that underlie addiction.
Ruairi Mackenzie (RM): How do these of learning and memory underlie drug addiction in the brain?
Professor Barry Everitt (BE): Very often, the feeling people have about being addicted to drugs is – if we focus on legal, readily available drugs like alcohol or tobacco – that they are available and that you just start using them and you can become addicted or you might have controlled use. But what actually goes on in an individual’s life who is addicted to drugs? Because the drugs aren’t always just immediately available. If we are talking about illicit drugs like cocaine, you have to acquire them in order to use them. That can be quite dangerous. When people are addicted, they act in a way that we describe as being compulsive. They will risk enormous harms to get those drugs. They may have to steal or work to get money in order to buy drugs, risk danger in then interacting with someone who will give them those drugs and then comes the actual moment of use.
To understand that we need to understand what it is in behavior that has to happen in order to acquire and then to take drugs and what might influence that. In that sense, it’s really no different to acquiring and eating food. In psychology and in behavioral neuroscience, for example, in experimental work with animals as well as humans, there are things called instrumental actions where you operate on the environment in order to get rewards. Very often, those actions become automatized – we all have habits. Many people will talk about smoking or drinking as a bad habit. Not necessarily implying complete loss of control in compulsion but doing it more than you should. Those are well understood terms in psychology that are experimentally testable.
The other big thing that’s become apparent is that when people take drugs, they tend to do so under a restricted set of circumstances. Stimuli in the outside world which are otherwise quite innocuous become reliably associated with the drug effect through Pavlovian conditioning. In the sense of people using drugs, these drug cues, let’s call them, can elicit craving. Thereby, they can precipitate relapse, but they can also elicit patterns of behavior focused on obtaining the drug. In the brain, there are systems of learning and memory that mediate Pavlovian conditioning and the impact of Pavlovian drug cues on instrumental behavior, which is performed while acquiring a goal drug. That’s how we approach the experimental analysis of addiction.
RM: I can see two ways of investigating this. Maybe understanding the neural systems would lead to information about how to change stimuli in the environment to reduce chance of relapse. Or perhaps, there could be some pharmacological way we could alter the brain itself to make it less prone to addiction. Are these avenues that have been explored?
BE: They are. In our own work, experimentally, we’ve certainly demonstrated that there are various classes of drug, some interacting with the dopamine system. Another drug, not commercially available, is an antagonist of one of the μ-opioid receptors. These profoundly diminish the effect that drug cues have in eliciting drug-seeking. If you pre-treat animals with those drugs, it diminishes their propensity to seek and therefore take drugs. At least one of those drugs, this opioid receptor antagonist, we know decreases the impact of alcohol cues in the brain in human imaging studies. There clearly are pharmacological ways of decreasing the likelihood that people will tend to forage for drugs, including when they’ve been abstinent and encounter cues that might precipitate relapse. You might ask well, why aren’t these available as treatments?
The answer, I’m afraid, is that big pharmaceutical companies that develop drugs have never really been in the game of developing treatments for addiction. This is possibly related to the popular belief that being addicted is just a failure of the will. That you should just say no to drugs, without stopping to think that maybe, some people can’t say no drugs because they’re impelled either by their personality or by stimuli in the environment. The other notion is that, maybe it’s not such a big market. I think that’s wrong, if we take alcohol and tobacco into consideration. But there’s not been a strong feeling within pharma that this is a good avenue to develop medicines for because it would cost billions of dollars or pounds over many years. In fact, it’s not only treatments for addiction. I mean, since the financial crash in 2008, big pharmaceutical companies have largely dropped out of the domain of psychiatric drug development.
BE: There are very few companies developing truly novel antidepressants, novel antipsychotics and novel anxiolytics. All we really have are the drugs that emanated from the bursts of development of those treatments in the ‘60s and ‘70s and refinements of those drugs in terms of increasing tolerance to them and reducing side-effects, rather than novel targets. Psychiatric drug development is challenging and there have been many examples of years of development with great potential which have not translated into effective treatments. It’s probably, in part, because there are many different types of depression and many different types of anxiety and many different types of addiction. There isn’t going to be a blockbuster drug. It’s going to have to be tailored, in the case of drug addiction, for different kinds of people using different drugs for different reasons. It’s complicated.
In my lecture, I discussed the evidence of compulsivity reflecting diminished executive control over behavior. Very often, many of us know that doing something is going to be not good for us, if not now, in the future. So, we don’t do it; we have inhibitory control. There’s a lot of evidence that people addicted to drugs don’t have that. The possibility emerges that maybe you could increase inhibitory control. Possibly by cognitive behavioral techniques, although these are very time demanding. But one of my colleagues in the states, at the National Institute on Drug Abuse, Antonello Bonci, who was one of the first people to demonstrate evidence of decreased activity of neurons in the prefrontal cortex in addiction, has been engaged in a big clinical trial with cocaine addicts.
He’s based in Italy, using transcranial magnetic stimulation to activate the prefrontal cortex, which we know is quiet in the addicted brain. Indeed, the evidence is, for many volunteers in the study over quite long periods of time, they turn up with drug-free urines. They’re much more likely to abstain, having achieved abstinence. If you could decrease the proportion of recidivism through this kind of treatment... I think we’re at the beginning of this, but I think it’s an area where we’re going to see changes. I hope we’re going to see changes in the future.
RM: What causes some people to become addicted in this way when others don’t?
BE: Well, there’s no definitive answer to that. We know something about stimulant addiction, in experimental work with animals and in humans. Often, cocaine and amphetamine addicts are impulsive. I think there’s been a wide held belief that may be because they’re taking drugs that make you impulsive but in fact, it turns out that the trait of impulsivity, long before someone has ever taken drugs, predisposes those individuals to lose control over cocaine consumption. Impulsivity is a vulnerability factor for compulsive cocaine use. Interestingly, and we’ve done some studies on this, even though people addicted to heroin are sometimes impulsive when they’re addicted to heroin, there’s no evidence, at least from experimental work, that impulsivity predicts loss of control over heroin. Similarly, with alcohol, it’s more of a mixed picture. Impulsivity isn’t a vulnerability trait for everything, but it may be particularly important for stimulants.
George Koob, another colleague in the US, would say that physical and psychological pain predisposes users to loss of control over heroin because it relieves the pain. We’re looking at that in the opioid epidemic. There may be different traits we have that predispose you when you first take a drug to lose control. I think that’s the challenging and fascinating thing about vulnerability, is whilst probably any one of us that takes cocaine will have an increase in dopamine in the reward system in the brain, we don’t know what else in the brain results in a greater magnitude effect on a proportion of us which then are more likely to do it again and again and lose control.
RM: We’ve talked about addiction to drugs, but the term addiction is used quite a lot by policymakers. Not about drugs, but about sugar or social media. What’s happening in the brain when we consume those, and how is that fundamentally different from someone who’s addicted to, say, cocaine?
BE: Well, I think it’s fair to say we don’t know the definitive answer to that but there are clearly some commonalities. We know that people who, for example, are compulsive gamblers have changes in their dopamine reward system that are not dissimilar to addiction. They may be quantitatively different but there’s a hyper-responsiveness to rewards and increased responses of dopamine. For my purposes, I like to use the term compulsion rather than addiction because that describes the behavior rather than the subjective state. Rather than being addicted to gambling, people compulsively gamble, and they compulsively eat. Compulsive use of drugs is a characteristic of addiction. It may be a symptom of loss of executive control, leaving people unable to discount immediate rewards for later, better, less harmful rewards.
I think that analysis of the underlying circuitry is going to show the degree to which the brain mechanisms that underlie behavioral addictions and drug addictions are the same or different and if we can draw comparisons between the two. There’s a lot of comorbidity. Many compulsive gamblers also drink. Many cocaine addicts also use other drugs as well. I think there are going to be differences, there are going to be overlaps. Of course, if there were many commonalities, we could think of a common approach to treat them but that may not be the outcome.
RM: You’re the President-Elect of the US-based Society for Neuroscience (SfN), the first ever President-Elect from outside North America. When you start your term, what are the challenges and opportunities for neuroscience that you’re going to look to address?
BE: I think they’re the same challenges now as last year. [SfN] is an astonishing society. It’s a global society even though it’s based in Washington D.C., and 40% of the members are not from the US – it holds a very international meeting. How I came to be elected, I have no idea. It’s not something you campaign for. I discovered I was nominated, and I had to decide whether to stand for election. There clearly was the decision inside the nominating board – I don’t even know who was on that, actually.
But maybe as countries like the US, through the visa policy that’s emerged under Trump with banned countries and, I would say, in the UK, with our withdrawal from the EU, with this rising populism and nationalism, [my appointment] was a statement that neuroscience and neuroscience effort and discovery is global. It requires the free movement of ideas and the free movement of people to increase our understanding of the brain and to bring much needed treatments to people in neurology and psychiatry who need them. Maybe that explains a little bit about behind why I was chosen? I mean, there are many people better qualified than me to do this but why me?
Maybe it’s a statement about internationalism. I’ve been on their council for the last four years, I’ve no doubt it’s an outward looking society but maybe this is a little more of an overt statement and I would like, during my term, to emphasize the internationality of neuroscience. To make it clear that this is neuroscience without borders. Where discovery is not the domain of one country or one group of people. It relies on interactions and in free exchange of ideas and common endeavors in order to fundamentally understand the brain. Because out of that fundamental understanding will come understanding of the brain when it goes wrong and therefore, how to target treatment. Maybe that is one of the things that will bring the international big pharma back into this game because they are needed as partners in this effort to bring treatments to the clinic that really benefit people who are very seriously ill.