The mouse that couldn't get high

Feb 04 2009 Published by under Addiction

In the second out of three possible papers for journal club, I got this paper courtesy of Physioprof. And I'm very glad he sent it to me. I get tons of Tables of Contents in my inbox every day, but I tend not to go through them until I need a paper for Journal Club. But PP clearly has some lit search chops, and sent me this paper 45 minutes after it first came out. Hot off the presses, indeed. Clearly, PhysioProf understands Scicurious' Big Three: Sex, Drugs, and...ok, maybe there's only two. Thomsen et al. "Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice". The Journal of Neuroscience, 2009.
Hold on to your hats, ladies and gents. This is a great paper, but it's also more than a bit technical. I'll do my best, but if there's anything you don't understand, do not hesitate to give a shout.

I blog a lot about addiction, particularly about stimulants such as cocaine, and the neurotransmitters which underlie some of its effects, like dopamine. In this field, it's pretty much accepted as gospel that "increases in dopamine in the nucleus accumbens are responsible for the initial rewarding and reinforcing effects of cocaine". It's become such a fact to us that we barely even cite it anymore. Of course, that's sciencespeak. In non-sciencespeak, that means "increases in dopamine in a very small area of your brain are what make that first hit of cocaine so great and make you want to do more". Is dopamine responsible for addiction? Well, we technically can't say that. Sure, it's responsible for the initial high, but everyone knows (or is) someone who did drug A, B, or C, and never went back, so clearly the initial high isn't everything.
But the high is still a lot. After all, if that first drink didn't do something for you, who would go back? Alcohol is disgusting to most species until we're taught to enjoy it, and that first buzz certainly helps. And if it weren't for a buzz, who'd snort incredibly expensive white powder up their noses in the first place? So that high may not be the be all end all, but it's certainly a start. So what if you had a mouse...that couldn't get high?
I'm going to include some background here as to what dopamine and cocaine are and how they work, but if you want more in depth stuff, I have general information posts on both dopamine and cocaine, so please check them out! They can help you to understand stuff I might be breezing through here.
Ok, so the background:
Dopamine is one of the major neurotransmitters in the brain, a chemical messenger that crosses the spaces between cells (synapses) to deliver the message on to the next neuron down the line. Dopamine acts at several receptors, known as D1-D5, and the system also has something called the dopamine transporter (which we call the DAT). The dopamine transporter here is of the greatest interest. It is responsible for recycling dopamine from the synapse back into the neuron for re-use. Dopamine as a neurotransmitter is implicated in lots of things, including drug addiction, Parkinson's, schizophrenia, motor disorders of various types, and possibly even depression.


Cocaine is what we science people like to call a psychostimulant, something that stimulates your brain. In particular, cocaine increases levels of three major neurotransmitters in your brain: dopamine, serotonin, and norepinephrine. Right now it is believed that it's the stimulation of the dopamine system that makes cocaine the powerfully addicting drug that it is. Cocaine blocks the reuptake of these neurotransmitters from the synapse by blocking the DAT (and the serotonin and norepinephrine transporters), and increasing the amounts of dopamine floating around in the synapse. The practical upshot of this is that you get nice and high.
Scientists have been playing with mouse genes for years now, and about 12 years ago, they created the dopamine transporter knockout mouse (we call it the DAT-KO). These mice have no dopamine transporter, and so nothing to help recycle the dopamine from the synapse when it's not needed. This means that these mice have TONS of dopamine constantly sitting around in the synapses of their brains. Not surprisingly, it shows up in their behavior. These mice are super-hyper, capable of jumping up and down in place for hours on end, due to all the dopamine in their system influencing their movement.
When these mice were first made, everyone wanted to give them cocaine and see what would happen. After all, if cocaine has its effects by blocking the DAT, and these mice don't have a DAT, then cocaine shouldn't work, the mice shouldn't like it, cocaine is all about its effects on dopamine, QED. So imagine everyone's surprise when these DAT-KO mice shot themselves up with cocaine! They also showed preference for cocaine in behavioral tests! (Rocha, 1998, Sora, 1998) Dopamine researchers were suddenly spending a lot of their time in bars, drinking heavily and asking existential questions about their career choices. If these mice self-administered cocaine, what was the point of cocaine hitting the DAT? Did this mean that the dopamine theory of addiction was wrong?
The real problem was that DAT-KO mice were finding cocaine rewarding, but without the DAT, cocaine should not have been able to increase DA levels in the brain. If cocaine was rewarding WITHOUT increasing DA levels in the brain, the dopamine theory of addiction was wrong, and a bunch of scientists were going to have to stop going to things like "dopamine dinners" and "the international conference on dopamine".
But it turned out that these mice had a twisted dopamine system (not to mention a twisted sense of humor in making scientists drink themselves under the table). The mice that self-administered cocaine STILL had a dopamine response. But without the DAT around, the dopamine was increasing because of the effects of cocaine on SEROTONIN. This shocked a whole bunch of people, but it also gave many peace of mind. Cocaine was acting on serotonin, but the end result was still an increase in dopamine in the nucleus accumbens. The dopamine theory of addiction still held (Mateo, 2004).
And now we come to this week. This study also looked at DAT-KO mice. And these mice, unlike the mice in the previous studies, DIDN'T like cocaine. Only a couple of them self-administered it, and they didn't seem particularly enthusiastic. But it wasn't lever pressing that was the problem, when tested with food, the DAT-KO mice responded just like normal mice.
A note on cocaine self-administration in rodents: take a rat or mouse. Put a port in it's back (where it can't reach), into the port put a catheter reaching around and into the jugular vein. Attach the catheter to a pump with a syringe. Fill the syringe with cocaine. Give the rat or mouse a lever, which is connected to the pump. When the animal presses the level, *poof*, shot of cocaine in the back. This also works for heroin, ethanol, morphine, amphetamine, or basically any other drug that's ever gotten a human high. So when we say "cocaine self-administration" this is what we mean. end of aside
So the DAT-KO mice didn't self-administer cocaine. But they DID self administer direct dopamine system agonists (drugs that act at dopamine receptors, mimicing the actions of dopamine). This showed very nicely that cocaine wasn't working, not because of problems with the dopamine system, but because there was no DAT present. Previous studies had also found that these DAT-KO mice had no increases in dopamine associated with cocaine, unlike the findings from previous studies.
What does all this MEAN? Is the dopamine theory of addiction still intact? Actually, YES. Here's the deal: the dopamine theory of addiction states that the initial rewarding and reinforcing effects of drugs like cocaine are due to increases in dopamine. So drug self-administration should accompany a dopamine increase. In the previous work, the DAT-KO mice did self-administer cocaine, but they ALSO showed increases in dopamine, though apparently serotonin was serving as the power behind the throne. In THESE DAT-KO mice (the ones in this study) there was no self-administration of cocaine, but there was ALSO no increase in dopamine! This still means that drug self-administration is correlated with an increase in dopamine. *phew* The stimulant researchers can breathe a sigh of relief and keep writing their grants. For now.
Wait a minute. One set of mice self-administered cocaine. One set didn't. But they are BOTH DAT-KO mice. Not only that, they're from the same strain of mice! What could be going on? Right now, people aren't sure. But we do know that different stem cells were used to create each mouse line, and that, though levels of dopamine receptors and levels of dopamine looked the same, the mice are obviously different. After all, one group self-administers cocaine, the other doesn't. Right now, the authors think that the stem cells could make the difference. Alternatively, it could be something about the way the knockout of the DAT was done, and what kind of adaptations the brains of these mice have gone through as they grew up. After all, you don't grow up with no DAT without some things changing. It could be that these different strains had different ways of coping with the loss of their DAT.
What's really clear is that more experiments need to be done, not on whether DAT-KOs self-administer cocaine, but on what makes these mice different from each other. The adaptations they have could be very important for humans. After all, some humans go around with their DATs chronically blocked, such as those addicted to stimulants. These people may adapt in different ways, and these mice could give us some clues as to how. In the meantime, these mice have already given us plenty to chew on.
M. Thomsen, F. S. Hall, G. R. Uhl, S. B. Caine (2009). Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice Journal of Neuroscience, 29 (4), 1087-1092 DOI: 10.1523/jneurosci.4037-08.2009

9 responses so far

  • DrugMonkey says:

    Very nice dissection of the issues scicurious, bravo!

  • HP says:

    The Mouse Who Couldn't Get High
    Once upon a time there lived a little mouse. She had beautiful white fur, and beautiful red eyes, and had a beautiful genetic modification that knocked out her dopamine transporter. Everyone called her Pinkeye. Pinkeye lived in the Kingdom of Lab, which was ruled over by the evil Prince Ipple Investigator.
    One day, the Prince appeared, and he called for Pinkeye, and she was very afraid. "Pinkeye," said the Prince, "You are not pressing your lever! All the other mice press their levers. Why do you not press yours?"
    "Oh, I am sorry, your highness," said Pinkeye. "I do not press my lever because I cannot get high."
    "Cannot get high?!" roared the Prince. "My lab is a lab for mice who can get high! You must leave my lab at once. Begone."
    And so, tearfully, Pinkeye left the Kingdom of Lab and went out to find her place in the world. She soon came to a huge mansion, made of stucco and red tile shingles, and inside was a Big Hollywood Party. And she was tired, and hungry, and so she went inside.
    "Ho-ho, little mouse," said the Hollywood Producer. "Why have you come into my house?"
    "I want to get high," said Pinkeye.
    And so the Hollywood Producer offered her the finest liquors, and Cuban tobacco, and pharmeceutical grade drugs, and purest, shimmering powdered cocaine.
    "Ho-ho, little mouse," said the Hollywood Producer. "How do you feel now?"
    "I am very grateful for your kind hospitality, sir," said Pinkeye. "But I cannot get high."
    And the producer said, "I am very sorry, little mouse, but my party is a party for mice who can get high. You must leave."
    Pinkeye left, and walked what seemed like a very long time, when she came upon a Crack Den. And although the house was run down and very scary, she was tired and hungry, and went inside.
    "Ho-ho, little mouse," said the Crack Dealer. "What do you need? Whatever it may be, I have got the hookup."
    "I would like to get high," said Pinkeye.
    And so the Crack Dealer offered her gallons of Robitussin, some stale barbecue potato chips, and a large rock of cheap crack.
    "Ho-ho, little mouse," said the Crack Dealer. "How do you feel now?"
    "I am very grateful for your kind hospitality, sir," said Pinkeye. "But I cannot get high."
    "My crack den is a crack den for mice who can get high," said the Crack Dealer. "You must leave at once."
    Soon Pinkeye came to a third house. It was built all of steel and glass, and looked very much like the Kingdom of Lab. She did not want to return to her home, but she was tired, and hungry, and so she went inside.
    "Ho-ho, little mouse," said the Man in the White Coat. "What brings you here?"
    "I would like to get high," said Pinkeye.
    "Did you try the lab down the street?" asked the Man in the White Coat.
    "Oh, yes. They put me through a series of controlled clinical trials, but I could not get high."
    "Did you try at the Big Hollywood Party?" asked the Man in the White Coat.
    "Oh, yes. They offered me every expensive thing, and pure, shimmering cocaine, but I could not get high."
    "Did you try at the Crack Den?" asked the Man in the White Coat.
    "Oh, yes. They offered me purple drank and stale chips and a big rock of crack. But I could not get high."
    "Oh-ho, little mouse," said the Man in the White Coat. "My lab is a lab for mice who cannot get high. I would like to investigate you further. Would you like come and stay with me forever?"
    Pinkeye didn't like the sound of that word, "lab," but she was tired, and hungry, and so she said, "Yes." And there she lived happily until the day of her necropsy.
    Moral: No matter what your problem is, someone will always find a way to exploit it.

  • JLK says:

    You explained that beautifully, Sci. I understood everything perfectly, despite my woefully handicapped understanding of neurochemistry and the like. I think this should be the paper you present, personally.
    But as an aside: "And so the Hollywood Producer offered her the finest liquors, and Cuban tobacco, and pharmeceutical grade drugs, and purest, shimmering powdered cocaine."
    Cuban tobacco can get you high?? I thought they got their tobacco from here! I'm still sittin' on a few Cuban cigars from my vacation, but I've only smoked one and I was so drunk at the time I wouldn't have noticed if it had any effect! lol

  • leigh says:

    oh how i love a good pharmacology story. circumventing the KO by throwing in direct agonist- perfect!

  • Scicurious says:

    It is indeed lovely, leigh. But I was wondering about a section of the paper I didn't cover. They ALSO did some tests on SERT-KO, and ran a dose-response curve on a D1 ANTAGONIST. They got a nice curve, but I was wondering why they did it, as well as why they didn't do the same in a DAT-KO to see if you could get self-admin at the highest dose. Just a thought.

  • Morgane says:

    I think I can answer that question...
    The SERT ko mice self-administered cocaine just like the wild-type controls, and we were poking around for any evidence that they differed from wt in cocaine self-administration. Dopamine antagonists produce, as one might expect, a rightward shift in cocaine self-administration dose-effect curves. Or, for a high dose of cocaine, increases in response rate (that are generally interpreted as the mouse compensating for a blockade of the reinforcing effect of cocaine, or as a blockade of rate-decreasing effects of cocaine, or a combination of both). The SERT ko mice responded just like you would expect, and like what earlier experiments have shown with wild-type mice. Thus, simply put, SERT mice appear to be quite normal as far as cocaine self-administration goes: they take it, and dopamine receptor activation is needed for the "high", as you put it.
    The DAT ko mice did not self-administer cocaine, and so there was no behavior to block or modulate with an antagonist.

  • Scicurious says:

    Morgane: are you THE Morgane? As in the paper's first author? I'm so thrilled to get your comment! Thanks so much for answering my question. I really like this paper, it's very well done.
    I was wondering, though. You did get a couple of the DAT-KOs to self-administer on on a FR1, though it didn't hold up and they didn't get adequate break points on the PR schedule. Do you think those few mice who did obtain self-administration might respond to a D1 antagonist?

  • Alanna says:

    I recently came across your blog and have been reading along. I thought I would leave my first comment. I don't know what to say except that I have enjoyed reading. Nice blog. I will keep visiting this blog very often.

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