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:
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:
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
