Why is Addiction a Brain Disease?

I started as a contributor for the blog network addictionblog.org.

addiction blog logo copy

Read my first post, published today!


Response to HuffPost Marc Lewis Interview on Addiction





Q: What’s wrong with the disease model of addiction? 

























Q: So what can we do about that?







Childhood Abuse Has Long-lasting Effects on Brain Function

(© Derek Simon 2015)
(© Derek Simon 2015)







fMRI Image (wikipedia.org)
fMRI Image (wikipedia.org)


Elsey et al. Neuropsychopharm. 2015





 Elton et al. Addiction Biol. 2014






Stress and Addiction Part 3: Molecular Changes


Paper #1 Sorg 1991. Title



Figure 1.
Figure 1.



Sorg 1991. Figure 2
Figure 2.


Paper #2

Zhou 1996. Title


Figure 1.
Figure 1.





Figure 2.
Figure 2.



Paper #3

Boyson 2014. Title



Figure 1.
Figure 1.


Figure 2.
Figure 2.







Q & A

Some questions about the research you might have and my answers:





Q: Can stress trigger relapse?



Next time: Doping on Dopamine.

Stress and Addiction Part 2: Early Life Stress and the Susceptibility to Addiction


This is part 2 of a series that deals with Stress and Addiction. It one part of a multi-part series of posts in which I attempt to provide a detailed analysis of all facets of one the most important questions in the addiction field: Why does one person become and an addict and another does not?

In Part 1 I showed how some forms of stress used in the laboratory, tail-pinch and social-stress, were able to increase the amount of psychostimulants self-administered by rats. Let’s expand this discussion to consider stress that may have parallels in human society.

Note: It is important to keep in mind that l am not making the claiming that stress exposure is the cause of addiction. I am merely providing evidence that your environment, specifically stress exposure, can increase your susceptibility to becoming an addict.

Can stress during childhood effect your susceptibility to becoming a drug addict?

It’s an intriguing question with many societal implications, given the disparities in the environments that children from different socio-economic backgrounds experience in the United States (I recommend reading Jonathan Kozol if you’re interested in learning about these disparities). But I’m not a sociologist, economist, public policy expert, etc. so I’m not capable of giving you my professional opinion on all the facets of this complicated issue but I can discuss the science behind the effects of early-life stress on drug-taking behavior.

Paper #1

Title. Kosten et al. Brain Res. 2000

This first paper looks at rats and the effects of stress during very early life on self-administration of cocaine as an adult but first, a little primer on the rodent life cycle. Rats and mice are mammals and like all mammals, give birth to live young. Litter size can be anywhere from 4-8 depending on the strain of animal. Animals born in the same litter are called littermates (note: this term doesn’t really have a human equivalent since humans typically only give birth to a single child at a time. Though we do have the terms twins, triplets, etc.).

Newborn animals (including humans) are called neonates. The mother rodent will then nurture her pups but feeding them breast milk through her nipples. All mammals are raised in this manner (even whales). This generally occurs for about three weeks in mice. In the lab, pups are then separated from the mother by the scientist, so they can become acclimated to an adult diet (i.e. not breast milk) but naturally, young mice will stop drinking breast milk once they are old enough The process of switching from breast milk to solid foods is a called weaning. Rodents are still considered in the adolescent stage for another three weeks after weaning. They go through puberty—the biological process in which mammals reach sexual maturity—at about 6-7 weeks of age and are then considered adults. *Note: these approximate times are for mice. Rat stages fall a little later.

The first study stresses rats during the neonatal phase by handling the newborn pups and separating them from their mother for 1 hour a day for days 2-9 after the date of birth. The authors call this neonatal isolation stress. The rats are then allowed to reach adulthood. At day 100 (3 months after the end of neonatal isolation stress) the stressed rats and rats from the same litter that were not handled (control group) underwent catheter implantation surgeries and then were tested for acquisition of cocaine self-administration for several didn’t doses.

Figure 1.
Figure 1.

Interestingly, as shown in Figure 1, the rats that underwent the neonatal isolation stress self-administered more cocaine at lower doses (0.125mg/nose poke) and 0.25mg/nose poke). However, this effect was not seen at a higher dose (0.5mg/nose poke). These experiments suggest that early life stress can have an effect on adult rats and increases the pleasure they get from the drug and makes them more likely to self-administer cocaine at a dose they otherwise might not be interested in. The self-administration data are summarized in Figure 2.

Figure 2.
Figure 2.

What’s really fascinating is how a relatively brief period of stress (1hr a day for 7 days) can have such a drastic effect on the rats’ behavior 100 days later! This study suggests that stress during early life can have permanent (or at least, very long lasting) effects on brain function.

Paper #2

Title. Baarendse PJJ et al. 2011The second study takes a similar approach but looks at different developmental time period. This study isolates rats (meaning rats are placed in individual cages rather than with their littermates) during adolescence, days 24-42 after birth (the experimental group, ISO). The control animals were socially housed during this time (SOC). This time frame falls after weaning but before puberty. On day 43, ISO animals were than housed together and a few weeks later, at 12weeks of age (well into adulthood) ISO and SOC rats were tested for self-administration of cocaine.

Figure 1.
Figure 1.

Similar to the other study, the authors found that isolated rats acquired cocaine self-administration at a low dose of cocaine (0.0625mg/nose poke), which means that animals that underwent the social isolation stress self-administered more cocaine at a low dose when compared to the socially housed control animals. This is seen in the left half of the graphs in Figure 1 (the left panel shows nose pokes while the right panels shows the total amount of drug self-administered). However, at a higher dose of cocaine (0.25mg/nose poke), the right half of the graphs in Figure 1, there was no difference in self-administration between the two groups.

Figure 2.
Figure 2.

Importantly, the isolation stress also had an impact on motivation to take the drug. In the next experiment, rats were tested on a progressive ratio self-administration where they have to nose poke multiple times in order to get a single dose of drug. The number of pokes required increases everyday until the rat is no longer willing to try to get the drug. This limit where the animal gives up is called the break point and it is a measure of how hard the animal is willing to work to get the drug (ie how motivated is the animal for the drug).

As you can see in Figure 2, rats that underwent the social isolation stress during adolescence had higher break points, which indicates they were willing to nose poke more times in order to get the drug (more motivated).

In summary: these experiments also showed that stress that occurs early in the rats life (during adolescence) can have a long lasting impact on the rat brain. The stress made the rats more likely—more susceptible—to acquire self-administration behavior. That is to say, early life stress caused the drug to appear to be more pleasurable to those animals (they wanted to self-administer more of the drug) than for the control, socially housed animals.

In conclusion, these papers have shown that, in rats, stress during early life can have significant effects on an animal’s susceptibility to becoming an addict. Many other papers have identified similar findings. As I alluded to at the beginning of the post, this knowledge has disturbing implications for humans raised in drastically different environments.

However, let’s briefly discuss some caveats to these studies. You are probably wondering, “well, that’s good and well for rats, but has this effect been proven in humans?” First, one of the reasons we run these types of experiments in mice and rats because it is much easier to control for all the other variables that would make interpreting the experiment extremely difficult. Fortunately, we can’t take a bunch of kids, stress them out during their childhood, and then see how much drugs they take at as an adult! But there are other types of analyses and experiments that could be run using data gathered from the “real” world.

Are there studies in humans that confirm the animal studies, that early life stress can increase the susceptibility to addiction?

The answer is yes! Lots of them! I don’t have time to review them all but thankfully many other scientists have. Check out these two review papers for a summary of some these studies. If you are interested in stress and addiction studies in humans, please let me know! I would be happy to devote a post or two to this topic.

Title. Sinha. 2001

Title. Enoch M. 2011

Finally, I would just like to end on a broader point, these studies once again confirm how brain development during early life can have far-reaching effects on adult hood (many other fields look at the general top of early life brain development). Indeed, the conditions under which we are raised are an important contributor to how we turn out as adults. But let’s not forget the role of genetics (this will be saved for a future discussion)!

Next post I’ll wrap up the Stress and Addiction discussion by looking at some of the molecular details of how and why stress increases susceptibility to addiction.

 Thanks for reading!






What is Stress?



The Hypothalamic-Pituitary-Adrenal (HPA) Axis
The Hypothalamic-Pituitary-Adrenal (HPA) Axis





How do we know stress is important in addiction?



Paper #1

Piazza 1990. Title
Paper #1














Paper #2

Paper #2
Paper #2



Haney 1995. Fig 1











Thanks for reading  🙂

The Scientist’s Toolbox: Techniques in Addiction Research, Part 1

Lab Mice IMG_4102
(Image © Derek Simon 2015)

One of the most important questions that every scientist learns to ask is “How do you know that…?” As scientists, we are trained to be skeptical. When we consider a bit of research done by a colleague, before we are inclined to believe the data,  we need to be sure that they conducted the right experiments and that those experiments were done correctly. This doesn’t mean that scientists are stubborn or closed-minded. The reality is quite the opposite. Scientists are ready to incorporate new ideas and new results but first we need to know that the data are real. That’s what being a skeptic is all about: reserving judgment until you know all the facts.

The question “How do you know that..?” is one of the intellectual tools we use when considering whether or not data are real or not. This question has two parts: 1) how do you measure the thing that you interested in and 2) how do you know the effect you are seeing is actually based on what you think it is? What type of comparisons do you need to make in order to test the effect you’re interested in?

The first point of the question relies on special tools, equipment/technology, and experimental setups that are used to take measurements. For example, if you want to know how much a mouse likes taking a drug, then you need a way to measure how much drug it takes and how often it takes the drug (more on this in a bit). Today, I’ll go over a few of the tools that we use in addiction research.

The second part is more important (and more difficult to explain) but is really at the heart of the scientific method. It is all about experimental design and making sure you make the proper comparisons and analyses. I won’t discuss these details any more right now but will save this discussion for a future post.

Instead, let’s take a look at a few of the tools a scientist studying drug addiction has in his/her toolbox.

Locomotor Activity Test

The psychostimulants amphetamine and cocaine act in very similar ways and have very similar effects on the brain. We know that stimulants sort of “amp you up” or make you feel like you have more energy. Think of how you feel after drinking too much coffee. And what do you do when you have more energy? You tend to move around more (maybe you feel a little twitchy/antsy after too much of that coffee…). The same thing happens to mice and rats.

Locomotor Activity Test Chamber with a mouse. Image from UC-Davis Mind Institute (http://www.ucdmc.ucdavis.edu/mindinstitute/).

We can measure the amount of movement using a locomotor activity test. This test uses a special piece of equipment that uses light beams and a light-sensitive detector. Whenever the animal moves around the test box, the light beams are broken and the detector records that information. One way to analyze the data is by simply plotting beam-breaks (photo-cell counts are the same thing) that occur over the time of the test period. This way you have a measure of how much the animal moves around in a certain amount of time (more beam-breaks/time unit equals greater movement). A more sophisticated analysis of this same data can actually give you information on where in the box the animal spends its time. Does is just pace back and forth in a small area of the box or does it explore the entire chamber? This type of exploratory behavior data is valuable information and can be useful to other fields that may or may not study drug addiction. The general test for this exploratory behavioral analysis, regardless of speed of the movement caused by drugs, is the open field test.


Multiple test boxes with a computer that collects the data. Image from Douglas Mental Health Institute (http://www.douglas.qc.ca/page/neurophenotyping-motor-function).

An interesting phenomenon has been identified with psychostimulants. If you give an animal an injection of cocaine it will move around more compared to regular animals. But if you give it another dose of cocaine the next day it will move around even more than it did on the first day. This is called locomotor sensitization and is an important property of psychostimulants like amphetamine and cocaine.

The graphs below are real data that I took from a figure from one of our lab’s papers so you can see what locomotor sensitization looks like.

Cocaine-induced locomotor sensitization. Unterwald EM et al. J. Pharmacol. Expt. Ther. 1994.
Cocaine-induced locomotor sensitization. (Unterwald EM et al. J. Pharmacol. Expt. Ther. 1994.)

It’s a little hard to read but there are two groups of animals: one that receives cocaine injections (the top line) and the other that receives saline injections (the bottom line). Saline is a saltwater solution that is a standard control solution that has no biological effects. Each data point represents an average of several animals from each group. The baseline graph shows the locomotor activity before injections (no differences). As you can see, at day 1 the cocaine animals are already moving more than the saline group. This increase in movement continues over the 14 days of the experiment, evidence of locomotor sensitization.

This video shows an analysis of locomotor activity using video tracking software instead of light-beam breaks.


Locomotor activity is all good and well but not all drugs of abuse cause locomotor sensitization. More directly related to addiction in humans, how do we even know if the animal likes the drug or wants to take the drug? Humans addicts crave the drug and compulsively use it, meaning the desire to do the of the drug overpowers the addict’s self-control. Is there a way we can study this type of drug-taking behavior in animals? The answer is yes!

Self-administration is a very versatile and powerful technique used throughout the addiction field. This technique allows the animal to control whenever it takes the drug and however much it wants. We can study many different aspect of drug taking using self-administration.

A diagram for a typical self-administration chamber. Image from Med Associates (http://www.med-associates.com/).


The basic idea is is simple: The rodent (mouse or rat) is placed in a chamber and presented with two levers. If the mouse the presses one lever (the active lever) it receives a dose of drug but if it presses the other lever (inactive lever) it does not. The self-administration sessions are run for a set period of time and the number of presses is recorded for each lever. Over the course of several days the animal steadily increases the amount of lever presses, thus the amount of drug it takes. Meaning the animal learns how to take drug and then takes more and more of it. Just like a human addict would do!

Alternatively, the mouse can poke its nose at a special hole that acts just like the active lever. I’ll use “lever press” and “nose poke” interchangeably because they essentially mean the same thing.

Here’s a little cartoon I found on YouTube of a rat that is self-administering nicotine.


Here’s another video that shows a real mouse self-administering a natural reward (meaning not a drug of abuse but food in this case).


There are several important variations to this basic idea that help scientists to not only make the experiments easier to control and data better/easier to analyze, but allow different aspects of drug taking to be studied.

For example if you are studying alcohol addiction, then when the mouse presses the lever a spout may appear that allows the animal to drink the alcohol (the inactive lever produces a bottle of water only). This is perfect for testing alcohol self-administration because both humans and mice drink alcohol. But what if you want to study heroin or cocaine self-administration? Humans (nor mice) drink or eat these drugs. So how does the drug get delivered to the mouse when it presses the lever?

The answer is intravenous self-administration. In this version, a small surgery is performed where a small tube (a cathether) is threaded into the jugular vein of the animal. This tube is fixed to the mouse back and attached to another tube that is part of the self-administration apparatus. This time when the mouse hits the lever, a dose of drug is pumped directly into its vein! See the diagram and videos above for more details.

Intravenous self-administration has several advantages.

  • As explained above, it allows us to deliver drugs to animals that won’t take them orally.
  • It allows the drug to act immediately on the animal because the drug is being delivered directly into the bloodstream.
  • It allows us to control the dose of the drug. When the mouse hits the lever (or nose pokes) it receives a fixed amount of drug that the scientist decides on ahead of time. That way we know how much total drug the mouse takes during a single self-administration session.
  • There is no variability in whether the animal is receiving the full dose or not. For example, if the lever press results in a food pellet, there is no guarantee the animal will eat the whole thing. But if you set the self-administration apparatus to deliver 0.5mg of heroin every time the lever is pressed, then there is no doubt if the full 0.5mg dose is delivered to mouse ever time.

Warning: not for the squeamish! This video shows you how to do the catheter implantation surgery on a mouse that will be used for intravenous self-administration!

Finally, best of all, self-ad can be used to address many different types of questions related to different stages in the addiction cycle. Here I briefly describe some of the more common experimental questions and applications that self-ad can help to address.

  • Initial use and escalation of use. How much will the animal take when it is first exposed to the drug? Will the animal reach a ceiling in the amount of drug it will take in a single session?
  • Maintenance of drug taking. One cool variation is you can make it more difficult for the animal to get the same dose of drug. This is called a progressive ratio self-administration. For example, the animal may need to press the lever 5 times before it receives a dose. You can keep increasing the number of presses during each session to see how hard the animal will work for a dose. One way this experiment can be interpreted is how badly does the animal want the drug? Some animals will press the lever many, many times just to get a small dose. This type of behavior is similar to the intense cravings that human addicts can experience.
  • Extinction and Relapse. You can run a special type of experiment where you run a self-administration experiment like normal and then change it so that the active lever no longer gives the animal a dose of drug. Eventually, the animal presses the lever less and less as it learns that it will no longer get the drug. This is called extinction of self-administration. This is like being in a rehab clinic where you are prevented from taking the drug. However, after the extinction sessions, if the scientist gives the animal another does of drug this will causes animal to start pressing the lever at high rates again. This a called reinstatement of self-administration and is model of relapse. What other types of conditions or factors can cause reinstatement (relapse behavior)? This situation is just like an abstinent cocaine addict who may not be craving cocaine but if he/she takes even a single hit, this can be sufficient for that person to sink back into full-blown addiction.

Let’s take a look at some real data. The graph below is from a paper from our group that looks at oxycodone self-administration in mice.

Oxycodone self-administration by adult and adolescent mice. (Zhang Y et al. Neuropsychopharmacol. 2009.)


This study is interested in comparing oxycodone self-administration between adult mice and adolescent mice. As you can see, the number of nose pokes at the active hole (remember, same thing as a lever presses) increases during the course of the experiment (don’t worry about FR1 vs FR3) while the inactive hole is ignored, because it does not result in drug administration. Note that the nose pokes are plotted over the time of the administration sessions (2 hours) and that 9 sessions are run (one every day).


The types of experiments I’ve described so far are great ways of studies addictive behaviors but they don’t really tell you about what’s going on in the brain. These behavior experiments are useful in themselves but they are much more powerful if they can be combined with another type of experiment that gives you a window into what’s changing in the brain at the same time as the behaviors.

In my post Synapse to it, I described how neurotransmitters are released by the pre-synaptic neurons into the synaptic cleft so that they can act on receptors located on the post-synaptic neuron. Using microdialysis, you can sample the fluid that exists in the synaptic cleft and actually measure the amount of neurotransmitters being released!

This is an extremely difficult and very technically complicated technique and I will only go into the basics about it. First, the microdialysis probe is surgically placed into a region of the brain that you are interested in studying.

The microdialysis probe itself is like a very thin piece of tubing that allows the experimenter to flow fluid into it one side(inlet) and collect the fluid that flows out of the other side (outlet). At the tip of the probe (the part that’s actually inside the brain) is a special type of material that allows fluid from inside the brain to flow into the tubing (a semi-permeable membrane).

Schematic of a microdialysis probe. Image from Wikipedia.
Schematic of a microdialysis probe. Image from Wikipedia.

After the surgery, you run your behavioral experiment, and while you are doing that you start flowing fluid into the brain. The fluid that the microdialysis probe flows in is of a similar consistency to the fluid that exists naturally in the brain. As the fluid inside the probe moves through the tubing, it causes fluids in the brain to enter into the probe and through the tubing where it can be collected when it flows out of the tubing.

Let’s say you give an animal a drug that causes a neurotransmitter to be released in the brain region you are interested in. Then some of those released neurotransmitters will enter the microdialysis probe because some of the fluid that enters the probe is from the synaptic cleft.

You keep collecting fluid at different time points during your experiment. When the experiment is over, then you can use chemistry to determine what neurotransmitters are in the fluid you collected. Best of all, you can determine how much of those neurotransmitters you have! How you do actually use chemistry to do this is a very technical part of the procedure and is not important to this discussion.

And all that work gives you a nice graph of the neurotransmitters that are released at different times during your experiment.

Now for some real data. Below are figures from a paper that our lab produced that uses microdialysis to study release of the neurotransmitter dopamine.

Evidence of probe placement in the Caudate  Putamen. (Zhang Y et al. Brain Res. 2001.)
Evidence of probe placement in the caudate putamen. (Zhang Y et al. Brain Res. 2001.)


Cocaine-induced increase in DA. (Zhang Y et al. Brain Res. 2001.)


In this study, the effect of cocaine on dopamine release in a region of the brain called the caudate putamen is being studied. The first image shows you that the microdialysis probe was placed in the right area of the brain (the white line that pierces through the dark area is the tract in the caudate putamen). The graph shows that injection of cocaine (the arrows) causes an increase in dopamine release in this brain region. Interestingly, the dopamine levels have returned to normal by the end of the experiment. Note: C57Bl/6J is the strain of mouse used in this study.

These are just three of the techniques that are used in addiction research. But we scientists have very big toolboxes! I’ll to explain some more in a later post.

Feel free to contact me or comment if you have questions!

Thanks for reading 🙂



You can find the link to the full paper here.
