Recently, in response Johann Hari’s article on drug addiction for the Huffington Post, my friend and I got into a discussion about how scientists choose specific research methods in addictive disorders. The article argues that the roots of drug addiction can be found in the lack of human connection, and so my friend questioned the methods used to study drug addiction, proposing that both social connection and brain chemistry contribute to drug abuse—and he’s right. Yet research into addiction from a neurobiological perspective is and will remain a key lens through which we’ll come to understand more and more about drug addiction and its consequences.

Millions of individuals suffer from drug addiction, and treatment options are limited. For the leading drug of abuse in the U.S., the Center for Disease Control and Prevention reports 16.6 million adults in the U.S. had an alcohol use disorder in 2013, and these numbers are not going down despite the number of treatment options currently available. Research on drug addiction is important for finding potential treatments that can be more effective by targeting specific causes of drug addiction. But before identifying those targets, we first must understand the driving forces behind drug addiction.

But What is Drug Addiction?

Not everyone who takes drugs becomes addicted. According to prevailing theories in drug addiction, there is a process that involves multiple phases with changing motivations to take the drug. Let’s use coffee as an example.

Phase 1: Binge Drinking

When I was younger, I hated coffee because it was very bitter, and I saw no benefit to drinking something that tasted like mud. I would have a couple sips from my mom’s mug in the morning and stick my tongue out with disgust. That was before my “coffee addiction” began. During college, I disguised the bitter taste of coffee with copious amounts of milk and sugar to reap the benefits of caffeine to stay awake and study late into the night. My coffee habit was being positively reinforced because I wanted to add great feelings of alertness and later the good grades I received after studying so much. Sometimes, I would even have extra coffee and feel hyper. This would be the binge-intoxication phase of the addiction cycle in which the person who consumes drugs in excess is being motivated by good experiences or rewards. The binge-intoxication phase can also be motivated by the subject wanting to avoid bad consequences.

Phase 2: The Down Side

Now that I am in grad school, I drink coffee every morning to feel awake and ready to tackle the day’s problems. I quickly learned that if I don’t get my coffee fix in the morning, I feel more tired and groggy, and I get a splitting headache later in the day. This is the withdrawal-negative affect phase of the addiction cycle. So to avoid those awful feelings, I continue to drink my coffee in the morning. Now my coffee habit is being negatively reinforced because I reduce the pain and tiredness that I experience when I don’t have coffee.

Phase 3: I Want More

In grad school, I go to a lot of talks and conferences where I have to be awake and pay attention. Whenever I have a lecture scheduled, I start thinking about when and where I can get coffee beforehand. I also get excited when I know there is going to be free coffee provided at a lecture. This is the preoccupation-anticipation phase of the addiction cycle during which I associate certain things (lectures) with coffee drinking (also called conditioned reinforcement, e.g., Pavlov’s dogs). I can go through multiple iterations of this cycle: I’ll drink coffee for its benefits, then I’ll drink more coffee to avoid the headaches, then I’ll try to stop drinking coffee some days, and on those days I think about the next time I plan to go to lecture and get free coffee, and then I go buy coffee to stay awake again.

1

In the same way that I have learned about my coffee drinking habit, scientists can set up experiments to explore different phases of the addiction cycle. These experiments help us map brain function (above) to certain phases of addiction. Many studies show that as one spirals down the cycle of addiction, the brain goes through different biochemical changes that drives behavior to continue the cycle.

In the article my friend read, there is an alternative theory that a person’s environment, especially social interactions, contribute more to addictive behaviors than brain chemistry. The truth is that there are multiple factors that can drive or prevent drug addiction, and scientists are still trying to understand all those factors. The ongoing scientific research can contribute to new therapies to reduce drug abuse by targeting specific causes. Now that we understand the different phases of drug addiction, we can mimic those phases in the laboratory to identify those targets for new therapies.

Models of Drug Taking

Scientists often use animals, usually rodents, in experiments if we want to understand changes in brain chemistry at specific points of addiction. This is difficult to do in humans, but the reward-related brain circuits in rodents are similar to those humans, so rodents are a good model for what happens in humans. Rats and mice quickly learn how to perform a task in order to receive a drug, like cocaine and methamphetamine, which activate the reward circuits in the brain.

These animals can be readily trained in an operant chamber, a box where a specific action—like poking their nose into a hole or pressing a lever—can yield rewards like receiving a dose of the drug. Imagine an empty rat-sized room with a lamp, a speaker, a cup, and two levers sticking out of the wall. And every time you press the correct lever, the cup fills up with liquid that makes you feel good. Think of this training as the binge/intoxication phase of drug addiction. The animals can either drink a drug solution or get an intravenous injection through a tube that directly puts the drug into the bloodstream. Because the animal can control how much drug they get, we call this behavior self-administration.

By allowing self-administration, researchers can ask questions about how motivated the animal is to take the drug. The task can be made more difficult, thus requiring more motivation, by increasing the number of lever presses after each reward, a task called progressive ratio schedule. The progressive ratio schedule means that the animal would have to press more times in order to receive the same reward: for the first reward, the animal only has to press once, and for the next reward, the animal presses three times, and for the next reward, nine presses, and so on until the animal gives up and no longer wants to press 100 plus times for the next reward. If the animal is very motivated, it will press many times just for one hit, whereas the less motivated animal will give up pressing the lever if it is not receiving drugs.

2

Scientists can also change the amount of time between presses or pokes to see how patiently the animal will wait before self-administering again as a measure of impulsive behavior. This task requires a delayed response for a greater reward, so the impulsive animal will not be able to wait long enough and will press the lever too soon, while the less impulsive animal will wait a longer amount of time in order to get a bigger dose of drug.

3

To ask questions related to withdrawal and rehab, the animals can go through extinction sessions, which are like the drug taking sessions, but certain characteristics (e.g., shape and smell of the operant chamber) are changed: notably, no drug is delivered when the animal presses the lever. Over multiple sessions, the animal learns that lever pressing is useless and the number of times the lever is pressed decreases. How quickly the animal stops pressing the lever tells researchers how rapidly the animal is adapting to abstinence from the drug.

After extinction, animals typically go through reinstatement sessions to test for drug relapse. They are put in the exact same operant box where they originally took the drug, with the same cues like lights or sounds. But this time they don’t get any drug. In these reinstatement or relapse sessions, the number of times the animal presses the lever is a measure of how much the context (shape and smell of the box) and cues (lights and tones that turn on with the lever press) drive the animal to seek drugs despite the fact that they learned lever pressing doesn’t give drugs anymore from the extinction sessions or “rehab.” Researchers can look at the biochemical changes in the brain during reinstatement to examine the biology behind drug relapse. By controlling the drug dose and time spent in operant chambers, researchers can study drug use in animals to drive research that will ultimately uncover more about drug-use in human.

These are just a few methods that scientists use to study drug addiction. There are many other ways to understand the causes of addiction in both rodents and humans. When we read headlines, however, it is important to think about the appropriate methods being used to investigate the specific questions about drug addiction. Sometimes the study is only looking at one phase of addiction, whereas another study might want to study the long term effects of a drug long after a one-time drug exposure. The way animals receive drugs in these two cases would be different, and neither would be incorrect. Scientists are thoughtful in what methods to use in order to best explore the question being investigated.

Further reading:

Featured image by Sean Williams. http://cargocollective.com/seanings/Coffee-is-a-helluva-drug. Cartoons from Addiction Biology 11 (2006): 2-38. Republished courtesy of Melissa Galinato. Originally published with NeuWrite SD.

Image Credit: waferboard via flickr

About The Author

Avatar photo
Melissa Galinato

Melissa Galinato is a Ph.D. student in the UCSD Neurosciences Graduate Program. In Dr. Chitra Mandyam’s laboratory at The Scripps Research Institute, she studies the role of adult neurogenesis in drug addiction. When Melissa is not hiding in the vivarium doing behavioral experiments, she loves eating tacos at the beach and visiting giraffes at the zoo.