You people. You people and your REQUESTS. Requests to do things like blog more about opponent-process theory. Well. Sci hears you. She obeys. At least this time. And for all your drug addiction experts out there asking me to read Koob, I can assure you that I have read a LOT of Koob in my time. For those of you not necessarily familiar with the drug abuse lit, George Koob is considered one of the greatest minds in current drug abuse research, and has done a lot to conform the motivationally-focused opponent-process theory to the model of drug addiction that exists today. Guy even has a wikipedia entry! That’s how you know you’ve hit the big time.
And so, Sci continues her discussion of opponent-process theory in this second installment, with many thanks to Koob and his co-author, Le Moal.
Remember this?
You’ll need it.
When we talk about addiction, we need to be very careful about WHAT, exactly, we are talking about. Addiction in the colloquial sense actually isn’t addiction in the scientific sense in all cases.
So: drug addiction (excluding other addictions right now like food and sex and the internet) is characterized by a compulsion to seek and take the drug of choice, lack of control in limiting how much drug is taken, and a negative state when the drug is taken away. Keep in mind that addiction is also characterized by chronic relapse. The concept of chronic relapse is more than someone getting out of rehab and going back to the bottle, it’s every time someone drinks again after saying they’re not going to or drinks more than they said they were intending to.
So why is this important? It’s important because it distinguishes between drug ABUSE and drug ADDICTION. After all, about 10{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} of the population is going to try cocaine in their lifetime. But only some of those 10{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} will become addicted to the drug. What is the difference between those people, and the people who don’t become addicted? And what triggers the descent from controlled, occasional drug use to selling yourself for your next hit?
Obviously, there is more than one factor at work here. According to Koob and others, the main factors at work as someone become addicted to a drug include changes in your natural reward mechanisms, changes in your natural negative state mechanisms, and changes in your response to stress.
Natural Reward Mechanisms (I am SO HIGH right now)
As you probably know by now from my many posts on dopamine, it’s a very important neurotransmitter in the mechanisms of natural reward systems. It’s hypothesized right now that every drug of abuse activates the dopamine system at some level, whether they be via changing the dopamine transporter at the terminals like cocaine and amphetamine, or by activating dopamine neurons in the ventral tegmental area like alcohol and opioids. Keep in mind, though, that dopamine isn’t all there is. It’s also thought that serotonin, the neurotransmitters GABA, opioid peptides, and endogenous (meaning homegrown cannabinoids that naturally occur in your brain) cannabinoids also play a role in reward mechanisms.
As we all know by now, drugs of abuse hijack these natural reward systems, and feel a lot better than anything that you could get naturally. And this means that chronic exposure to drugs of abuse can alter your natural reward systems, meaning that the same circuits (like the dopamine system, for example) that are involved in the positive effects of drug taking, can become disrupted, a change called within-system neuroadaptation. The main neuroadaptation that takes place occurs with something that scientists like to call the “brain reward threshold”, which basically means how much stimulation is needed to cause your brain reward mechanisms to notice. When Sci thinks of ‘thresholds’, she thinks of stairs. So picture this:
Think of your normal brain reward threshold as shallow. It doesn’t take a lot of drug to make your brain go “dude, this feels GREAT!” However, after prolonged exposure, within-system neuroadaptations take place, and your reward threshold becomes steeper:
Obviously, it’s going to require more drug on board to get your brain reward mechanisms in on the action. We like to call this tolerance. In terms of our old opponent-process graph, it’s going to go from this:
To this:
It’s the same thing, you require more drug to get the same positive feelings you had before. Your brain reward system has become tolerant. This has been found to occur in humans. Cocaine addicts have low-functioning dopamine systems, and we think that this not only contributes to tolerance to the rewarding effects, but also contributes to the negative feelings associated with withdrawal.
Antireward Systems (what a downer)
Some people seem surprised that we have antireward systems, but really, it’s a no-brainer. You need to be aware when you don’t feel good, otherwise you’re not going to do anything to fix the situation. Unfortunately, this is another set of systems (and it’s many systems, involving regulation of emotional pain, irritability, pain perception, malaise, and motivation) that changes during a drug addicted state. When you first take a drug, the overactivation of the reward system induces the recruitment of the antireward system, tying to bring you back down from your high. These antireward systems often persist longer than the drug is onboard, resulting in the acute withdrawal seen with things like alcohol hangovers and the depression experienced after cocaine use. To get a little funky with the graph, think of an alcohol hangover:
The yellow is the positive effects, the red is the aversive effects. You can see that the positive effects of the drug peak before the antireward systems (in this case the effects of dehydration and nausea and other things induced by alcohol being on board) of your brain can get recruited, and that the antireward systems remain “on” after the drug effects are gone. The result? A hangover. In a longer term sense, there are other antireward mechanisms that get recruited and contribute to a negative state, things like increased anxiety and craving.
And these antireward systems become more sensitive over time, producing an aversive state that is triggered a lot faster this normal. This state of feeling crappy can actually drive drug abuse even more than the memory of how great the high was. Now you need the high produced by the drug, just to overcome your negative state and feel normal again. This contributes to the compulsive nature of drug addiction.
However, addicts don’t always crave drug. There are situations which set off the drug craving mechanisms, both those of positive reinforcement (remembering how good it was to get high), and those of the antireward mechanisms. The first of these situations what we like to call cue-related. And cue is a pretty broad term. Basically, a cue is anything that can remind you of past drug use. And if, say, you’re using the drug in your room, around your neighborhood, in your car, or with your friends, those cues can be really hard to avoid. Pretty soon, you’re remembering how good it was to get high, and you’ve relapsed. But there’s a second situation which gets recruited in drug addiction: stress.
The State of Stress (I’m so stressed OUT, I just need to RELAX)
Everyone’s heard about it before. An addict comes out of rehab, swearing they’ve seen the light, they hate their drug, and they’re never using again. And they mean it. They believe this very firmly. And then something happens. A family member gets sick, there’s a divorce, they lose their job, something. And then…relapse. This is another system that gets out of whack following chronic exposure to addictive drugs, the stress system.
This isn’t surprising. After all, negative states like withdrawal are…stressful. Negative states take a toll on the body and brain. Acute withdrawal is known to release chemicals in the brain associated with stress, such as corticotropic-releasing factor and norepinephrine. Not only that, these stress signals feed-forward to the antireward system, producing a negative state because you’re stressed, which in turn increases feelings of stress, and so on. What this means in addicts is that stress can trigger craving by producing feelings associated with drug withdrawal. And the next thing you know, you NEED that drug. Just once.
And this is currently how we think opponent process theory works with regard to addiction. It is called the allostatic model, referring to the changes that take place in the brain over the time in a drug addict, as the brain takes a continuous reevaluation of the situation (how stressed are you? how do you feel right now?), and acts accordingly, increasing or decreasing craving for a drug and changing the emotional setpoint. And there are some pictures that show this really well.
First, we have picture 1, the drug naive individual:
You can see this looks a bit better that my opponent-process diagrams, but the principle is the same. Following the exposure to the drug in the naive person, reward systems are activated, things like dopamine and opioids, and net affect is positive. Then, the drug effect fades, and negative feelings set in, activating stress systems. You get a hangover, or feel slightly bad, but it’s nothing extreme.
But now, see the drug-dependent individual:
This person is taking drug pretty continuously in order to avoid withdrawal. You can see at the beginning, on the left of the graph, their set point has been reset (0′ instead of 0), they feel crappy, and they take drug. But the positive effects of the drug are only just enough to overcome the negative set point, and then, when withdrawal kicks in, it’s more severe, and recovery is only partial, to the now, low set point where they always feel crappy.
But of course, some people aren’t high ALL the time, and alcoholics aren’t drunk ALL the time. Instead, they do something called drug-taking binges or episodes, and those end up looking like this:
Here you see that the person is set at a lower set point (0′), similar to figure B. But they aren’t doing drug continuously. Instead, they are set off by a stressor, which drives them even LOWER, to set point 2 (0″). Driven by stress and negative feelings, they take drug. But the normal dose of drug doesn’t even serve to get them high anymore. Rather, it just brings them up to a normal motivational state, which is quickly overcome by withdrawal, and they return to a motivational state no better than where they started.
But of course, many people taking drug have gone into long periods of abstinence, where they no longer crave the drug on a daily basis. How does relapse then occur?
Here’s a person in protracted abstinence. They don’t feel great, but they are still abstinent, and have been for a while. When they do take the drug (triggered either by drug cues or stress), they get high, and in fact get almost as high as they used to. But the antireward system states are still sensitized, and withdrawal is worse than you would see in a naive individual. Thus, they only return to a lower set point (0′). And then they either again become dependent to avoid withdrawal, or remain at the lower set point until a stressor comes along.
These pictures allow you to see how the set points of a persons emotions and motivations change over the course of drug addiction, and how these changes can contribute to continued use, or to relapse. And they highlight the fact that drug addiction is a chronic physiological disorder resulting in long term changes, and that these changed systems can be triggered by things in the environment or within the brain itself.
Koob, G., & Le Moal, M. (2008). Addiction and the Brain Antireward System Annual Review of Psychology, 59 (1), 29-53 DOI: 10.1146/annurev.psych.59.103006.093548
